https://embryology.med.unsw.edu.au/embryology/api.php?action=feedcontributions&user=Z3389343&feedformat=atomEmbryology - User contributions [en-gb]2024-03-28T12:52:58ZUser contributionsMediaWiki 1.39.6https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=79212User:Z33893432011-10-23T00:29:16Z<p>Z3389343: /* Lab 12 Assessment */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:05, 20 October 2011 (EST)<br />
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==Lab Assesments==<br />
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===Lab 1 Assessment===<br />
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1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
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In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
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2. Identify a recent paper on fertilisation and describe its key findings.<br />
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Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
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3. Identify 2 congenital anomalies.<br />
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Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
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1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
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In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
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2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
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Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
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Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
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Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
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*1. What is the maternal dietary requirement for late neural development?<br />
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Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
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*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
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[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
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*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
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It is continuous with the developing hindgut.<br />
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*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
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Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
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*3. Identify the Group project sub-section that you will be researching.<br />
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I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
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*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
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The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
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*What week of development do the palatal shelves fuse?<br />
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This occurs in week 9 of embryonic development.<br />
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*What animal model helped elucidate the neural crest origin and migration of cells?<br />
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This was the chick embryo.<br />
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*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
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This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
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*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
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===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
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*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
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===Lab 12 Assessment===<br />
*Give examples of 3 systems that continue to develop postnatally.<br />
Firstly, the nervous system continues to develop postnatally. While most of the wiring of the neurons in the central nervous system has been achieved prenatally, there is extensive remodeling and pruning of the neuronal connections during the early years of life.<br />
Secondly, the respiratory system continues to develop postnatally, as the lungs are collapsed and filled with fluid until birth. The liquid is replaced by air through respiratory movements.<br />
Thirdly, the cardiovascular system also continues development postnatally to adjust for the altered blood circulation that results after birth when the respiratory blood circulation is not bypassed anymore.<br />
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*Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.<br />
**Phenylketonuria ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=261600 OMIM])<br />
**Cystic Fibrosis<br />
**Congenital Adrenal Hyperplasia<br />
**Congenital Hypothyroidism<br />
**Galactosemia<br />
**Congenital Toxoplasmosis<br />
**Biotinidase Deficiency<br />
**Homocystinuria<br />
**Maple Syrup Urine Disease<br />
**Medium-Chain Acyl-CoA Dehydrogenase Deficiency<br />
**Toxoplasma gondii IgM antibodies<br />
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==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
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===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
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===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
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===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
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===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
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===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
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<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
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<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
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<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=79211User:Z33893432011-10-23T00:27:08Z<p>Z3389343: /* Lab 12 Assessment */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:05, 20 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
<br />
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*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
<br />
*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
<br />
*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
<br />
*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
<br />
The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
<br />
*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
<br />
*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
<br />
*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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<br />
===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
----<br />
--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
<br />
===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
<br />
===Lab 12 Assessment===<br />
*Give examples of 3 systems that continue to develop postnatally.<br />
Firstly, the nervous system continues to develop postnatally. While most of the wiring of the neurons in the central nervous system has been achieved prenatally, there is extensive remodeling and pruning of the neuronal connections during the early years of life.<br />
Secondly, the respiratory system continues to develop postnatally, as the lungs are collapsed and filled with fluid until birth. The liquid is replaced by air through respiratory movements.<br />
Thirdly, the cardiovascular system also continues development postnatally to adjust for the altered blood circulation that results after birth when the respiratory blood circulation is not bypassed anymore.<br />
<br />
*Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.<br />
**Phenylketonuria http://omim.org/entry/261600<br />
**Cystic Fibrosis<br />
**Congenital Adrenal Hyperplasia<br />
**Congenital Hypothyroidism<br />
**Galactosemia<br />
**Congenital Toxoplasmosis<br />
**Biotinidase Deficiency<br />
**Homocystinuria<br />
**Maple Syrup Urine Disease<br />
**Medium-Chain Acyl-CoA Dehydrogenase Deficiency<br />
**Toxoplasma gondii IgM antibodies<br />
<br />
==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
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<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
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<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
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<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=79098User:Z33893432011-10-21T06:30:28Z<p>Z3389343: /* Lab 12 Assessment */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:05, 20 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
<br />
<br />
*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
<br />
*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
<br />
*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
<br />
*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
<br />
The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
<br />
*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
<br />
*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
<br />
*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
<br />
===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
<br />
===Lab 12 Assessment===<br />
*Give examples of 3 systems that continue to develop postnatally.<br />
Firstly, the nervous system continues to develop postnatally. While most of the wiring of the neurons in the central nervous system has been achieved prenatally, there is extensive remodeling and pruning of the neuronal connections during the early years of life.<br />
Secondly, the respiratory system continues to develop postnatally, as the lungs are collapsed and filled with fluid until birth. The liquid is replaced by air through respiratory movements.<br />
Thirdly, the cardiovascular system also continues development postnatally to adjust for the altered blood circulation that results after birth when the respiratory blood circulation is not bypassed anymore.<br />
<br />
*Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.<br />
<br />
==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
----<br />
<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
----<br />
<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
----<br />
<br />
<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=79082User:Z33893432011-10-21T04:39:42Z<p>Z3389343: /* Lab Attendance */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:05, 20 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
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In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
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3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
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1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
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Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
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*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
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*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
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[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
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*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
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*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
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*3. Identify the Group project sub-section that you will be researching.<br />
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I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
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*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
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The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
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*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
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*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
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*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
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===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
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===Lab 12 Assessment===<br />
*Give examples of 3 systems that continue to develop postnatally.<br />
*Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.<br />
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==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
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===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
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<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
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<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
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<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=79081User:Z33893432011-10-21T04:39:17Z<p>Z3389343: /* Lab Attendance */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:05, 10 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
<br />
<br />
*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
<br />
*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
<br />
*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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===Lab 5 Assessment===<br />
<br />
*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
<br />
The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
<br />
*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
<br />
*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
<br />
*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
----<br />
--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
----<br />
--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
<br />
===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
<br />
===Lab 12 Assessment===<br />
*Give examples of 3 systems that continue to develop postnatally.<br />
*Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.<br />
<br />
==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
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<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
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===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
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<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=79080User:Z33893432011-10-21T04:38:03Z<p>Z3389343: /* Lab 12 Assessment */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
<br />
<br />
*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
<br />
*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
<br />
*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
<br />
*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
<br />
The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
<br />
*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
<br />
*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
<br />
*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
<br />
===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
<br />
===Lab 12 Assessment===<br />
*Give examples of 3 systems that continue to develop postnatally.<br />
*Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.<br />
<br />
==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
----<br />
<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
----<br />
<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
----<br />
<br />
<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=79079User:Z33893432011-10-21T04:37:24Z<p>Z3389343: /* Lab 11 Assessment */</p>
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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==Lab Assesments==<br />
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===Lab 1 Assessment===<br />
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1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
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In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
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2. Identify a recent paper on fertilisation and describe its key findings.<br />
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Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
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3. Identify 2 congenital anomalies.<br />
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Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
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1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
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In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
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2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
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Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
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Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
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Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
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*1. What is the maternal dietary requirement for late neural development?<br />
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Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
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*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
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[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
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*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
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It is continuous with the developing hindgut.<br />
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*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
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Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
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*3. Identify the Group project sub-section that you will be researching.<br />
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I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
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*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
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The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
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*What week of development do the palatal shelves fuse?<br />
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This occurs in week 9 of embryonic development.<br />
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*What animal model helped elucidate the neural crest origin and migration of cells?<br />
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This was the chick embryo.<br />
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*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
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This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
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*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
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===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
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*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
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===Lab 12 Assessment===<br />
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==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
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===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
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===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
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===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
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===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
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===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
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===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
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<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
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<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
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<br />
<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=78736User:Z33893432011-10-19T23:51:24Z<p>Z3389343: /* Lab 11 Assessment */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
<br />
<br />
*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
<br />
*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
<br />
*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
<br />
*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
<br />
The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
<br />
*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
<br />
*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
<br />
*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
<br />
===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, which leads to the obstruction of the blood flow to the lower body parts; coarctation of the aorta, characterised by a narrowing in the area where the ductus arteriosus inserts; and aortic stenosis, where the aortic valve doesn't open fully and thus restricts blood flow from the heart.<br />
<br />
==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
----<br />
<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
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===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
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Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=78671User:Z33893432011-10-19T07:06:25Z<p>Z3389343: /* Lab 11 Assessment */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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==Lab Assesments==<br />
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===Lab 1 Assessment===<br />
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1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
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In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
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2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
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3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
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1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
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<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
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*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
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*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
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[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
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*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
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*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
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*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
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*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
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The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
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*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
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*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
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*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
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===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
Abnormal development of the outflow tract can give rise to an interrupted aortic arch, coarctation of the aorta, aortic stenosis<br />
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==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
----<br />
<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
----<br />
<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
----<br />
<br />
<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=78670User:Z33893432011-10-19T07:01:31Z<p>Z3389343: /* Lab 11 Assessment */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
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Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
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Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
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Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
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*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
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[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
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*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
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Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
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*3. Identify the Group project sub-section that you will be researching.<br />
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I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
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*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
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The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
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*What week of development do the palatal shelves fuse?<br />
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This occurs in week 9 of embryonic development.<br />
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*What animal model helped elucidate the neural crest origin and migration of cells?<br />
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This was the chick embryo.<br />
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*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
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This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
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*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
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===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
The interatrial septum is formed through fusion of the muscular septum primum and the muscular septum secundum. During gestation, this fusion is incomplete and there is a large opening in each septum, allowing right-to-left shunting of the blood, thus bypassing the developing pulmonary system.<br />
The two passages that allow this blood flow during gestation, thus connecting right and left atria, are Foramen ovale and Foramen secundum.<br />
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*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
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==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
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===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
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===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
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===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
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===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
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===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
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<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
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<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
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<br />
<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=77884User:Z33893432011-10-13T03:12:39Z<p>Z3389343: /* Lab Assesments */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
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==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
<br />
<br />
*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
<br />
*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
<br />
*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
<br />
*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
<br />
The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
<br />
*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
<br />
*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
<br />
*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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===Lab 8 Assessment===<br />
Peer Assessment<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
<br />
===Lab 11 Assessment===<br />
*Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.<br />
*Identify the cardiac defects that arise through abnormal development of the outflow tract.<br />
<br />
==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
----<br />
<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
----<br />
<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
----<br />
<br />
<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=777842011 Group Project 82011-10-13T01:50:12Z<p>Z3389343: /* Inheritance */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
{|align="right"<br />
|-<br />
|[[File:GAA Frequency in FRDA.jpg|370px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|-<br />
|[[File:Symptoms and signs in FRDA patients.jpg|370px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
'''Distribution'''<br />
<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Pedigree of Friedreich's Ataxia.PNG|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']]. More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']], which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']], and thus preventing hypoacetylation<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
Histone deacetylase inhibitors (HDACI) have been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI returned the levels of genetic expression of the frataxin gene, responsible for the production of the frataxin protein, to normal. HDACI is able to cross the blood brain barrier and acetylate histones, furthermore tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebenone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebenone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebenone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
<br />
* [[Cardiac Embryology]] - Development of heart.<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
* [[Molecular Development - Genetics]] - The genetics and molecular mechanisms of development.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - More details about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Neonatal Diagnosis]] - More on genetic screening and neonatal diagnosis.<br />
<br />
* [[Neural - Cerebellum Development]] - This page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Acetylation''' - The process of adding an acetyl group into a compound. Acetylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Deacetylation''' - The removal of an acetyl group to a compound.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypoacetylation''' - Less acetylated than in normal circumstances.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Methylation''' - Enzymatic transfer of methyl groups to biological molecules, such as RNA and DNA. Methylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Pedigree_of_Friedreich%27s_Ataxia.PNG&diff=77782File:Pedigree of Friedreich's Ataxia.PNG2011-10-13T01:46:51Z<p>Z3389343: The pedigree of a family affected by Friedreich's Ataxia. Due to the anticipating nature of the inheritance, the severity of symptoms increases while the age of onset decreases with each generation. Heterozygous individuals who possess one allele with the</p>
<hr />
<div>The pedigree of a family affected by Friedreich's Ataxia. Due to the anticipating nature of the inheritance, the severity of symptoms increases while the age of onset decreases with each generation. Heterozygous individuals who possess one allele with the repeat expansion do not develop symptoms, and are thus unaffected carriers. The expression of Friedreich's Ataxia occurs only when an individual carries two mutated frataxin alleles. Please note that this pedigree is entirely fictional and solely serves as a model to illustrate the mode of inheritance.<br />
<br />
Copyright Beginning six months after publication, I (z3389343) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
<br />
Drawn by student z3389343.</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3389343&diff=77746User:Z33893432011-10-13T00:07:13Z<p>Z3389343: /* Lab Attendance */</p>
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<div>{{2011Student}}<br />
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--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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==Lab Attendance==<br />
--[[User:Z3389343|Z3389343]] 12:56, 28 July 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 11:06, 13 October 2011 (EST)<br />
<br />
==Lab Assesments==<br />
<br />
===Lab 1 Assessment===<br />
<br />
1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.<br />
<br />
In Vitro Fertilization was developed by Robert Edwards, for which he won the Nobel Prize in 2010. He started research on the biology of fertilization in the 1950s, and soon realized fertilization outside the body was a possible treatment for infertility. This had previously been proven successful in rabbits, therefore Edwards tried to use the same process in humans. He identified the processes related to the maturation of human eggs and when they could be fertilized. He further identified how sperm is activated. With collaboration of gynecologist Patrick Steptoe, they developed IVF for medical practice.<br />
Source: http://nobelprize.org/nobel_prizes/medicine/laureates/2010/press.html <br />
<br />
2. Identify a recent paper on fertilisation and describe its key findings.<br />
<br />
Pandian, Z., Bhattacharya, S., Ozturk, O., Serour, G., & Templeton, A. (2009). Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Chochrane Database of Systematic Reviews, 15.<br />
IVF pregnancies often result in multiple pregnancies due to multiple embryo transfers, which in turn can cause maternal and perinatal morbidity. In order to reduce this, single embryo transfers are considered and their pregnancy success rates are compared to multiple embryo transfers (MET). The researchers found that for a single fresh IVF cycle, single embryo transfer is associated with lower life birth rates (LBR) than dual embryo transfer, however statistically, there is no significant difference. There were not enough data to compare single embryo transfers to three or four embryo transfer policies.<br />
<br />
3. Identify 2 congenital anomalies.<br />
<br />
Polydactyly is a dysmelia; a limb defect, caracterised by the presence of additional fingers or toes.<br />
The atrial septal defect is an example of a heart congenital anomaly in which the blood can flow between the left and right atria via the interatrial septum. This is usually closed, forming a barrier between the two atria.<br />
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--[[User:Z3389343|z3389343]] 12:53, 4 August 2011 (EST)<br />
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===Lab 2 Assessment===<br />
<br />
1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation.<br />
<br />
In humans, there are three ZP proteins, ZP1, ZP3 and ZP4, that are known to bind to the capacitated spermatozoa and play a role in the induction of the acrosome reaction. (The ZP protein ZP2 has been found to only bind to acrosome-reacted spermatozoa.) After fertilisation, ZP protein ZP3 is known to undergo a conformational change, leading to the hardening of the zona pellucida, thus playing part in the prevention of polyspermy.<br />
<br />
<br />
2. Journal Articles:<br />
* Review about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research Article about Angelman Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
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--[[User:Z3389343|z3389343]] 21:12, 9 August 2011 (EST)<br />
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--[[User:Z3389343|z3389343]] 12:34, 11 August 2011 (EST)<br />
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[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg]]<br />
<br />
Differentially expressed RefSeq genes in human trisomy 21.jpg<br />
<br />
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080369/<br />
<br />
Figure 6 Differentially expressed RefSeq genes in human trisomy 21. (A) Standard MA-plot of the normalized global observed counts per each RefSeq gene. (B) shows the percentage of RefSeq genes classified as strong, good, acceptable evidence of DE with respect to those not showing any statistical evidence.<br />
<br />
Copyright Costa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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===Lab 3 Assessment===<br />
<br />
*1. What is the maternal dietary requirement for late neural development?<br />
<br />
Choline is critical critical for the development of the hippocampus and memory function. It influences stem cell proliferation and apoptosis, thus shaping brain development and function as well as neural tube development. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441939/<br />
<br />
<br />
*2. Upload a picture relating to you group project. Add to both the Group discussion and your online assessment page. Image must be renamed appropriately, citation on "Summary" window with link to original paper and copyright information. As outlined in the Practical class tutorial.<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice]]<br />
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--[[User:Z3389343|z3389343]] 11:09, 18 August 2011 (EST)<br />
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===Lab 4 Online Assessment===<br />
<br />
*1. The allantois, identified in the placental cord, is continuous with what anatomical structure?<br />
<br />
It is continuous with the developing hindgut.<br />
<br />
*2. Identify the 3 vascular shunts, and their location, in the embryonic circulation.<br />
<br />
Two of these vascular shunts are involved in shunting the pulmonary circulation: the foramen ovale shunts the blood from the right atrium to the left atrium, and the ductus arteriosis shunts the blood from the pulmonary artery to the aorta. The third shunt is the ductus venous in the liver, which shunts the blood from the umbilical blood directly to the heart's venous return.<br />
<br />
*3. Identify the Group project sub-section that you will be researching.<br />
<br />
I will be focusing on the genetics, as well as trying to find some information on the cellular and molecular mechanisms involved in the degradation of the neuromuscular junction and other synapses affected by the disease.<br />
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--[[User:Z3389343|z3389343]] 11:42, 25 August 2011 (EST)<br />
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===Lab 5 Assessment===<br />
<br />
*Which side (L/R) is most common for diaphragmatic hernia and why?<br />
<br />
The left side is the most common side as congenital diaphragmetic hernia is most commonly caused by a failure of the left pleuroperitoneal membrane to completely seal off the left pleural cavity from the peritoneal cavity.<br />
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--[[User:Z3389343|z3389343]] 11:41, 1 September 2011 (EST)<br />
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===Lab 6 Assessment===<br />
<br />
*What week of development do the palatal shelves fuse?<br />
<br />
This occurs in week 9 of embryonic development.<br />
<br />
*What animal model helped elucidate the neural crest origin and migration of cells?<br />
<br />
This was the chick embryo.<br />
<br />
*What abnormality results from neural crest not migrating into the cardiac outflow tract?<br />
<br />
This leads to deficient smooth muscle differentiation around aortic arch arteries. <ref><pubmed>15226263</pubmed></ref><br />
<br />
----<br />
--[[User:Z3389343|z3389343]] 11:18, 15 September 2011 (EST)<br />
----<br />
<br />
===Lab 7 Assessment===<br />
*1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?<br />
Satellite cells are not necessary for muscle hypertrophy as this can occur normally without satellite cells. However, satellite cell are normally involved in hypertrophy as satellite cell proliferation is a normal response to hypertrophy.<br />
*2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift?<br />
Fast twitch fibres use anaerobic metabolism to create the energy and are particularly good for short and sudden bursts of strength or speed. Slow twitch fibres in contrast use aerobic metabolism to produce slow, continuous muscle contractions. The fibre types are interchangeable (though this is not achieved in a single step but involves a slow shift). In a scenario of chronic low frequency stimulation, it would be the slow fibre types that would be active and most useful during the contraction while fast fibre types wouldn't be needed that much, and thus the fast to slow fibre type shift is an adaptation to the chronic low frequency stimulation to produce a more efficient response, mediated by slow fibre types.<br />
<br />
*Comments on the Trisomy 21 page:<br />
**The introduction could be a little bit longer, and maybe include a little bit of a historic timeline?<br />
**Having the recent findings follow the introduction immediately is confusing as the reader hasn't had a chance to learn anything about the condition yet, so can't really relate the recent findings to anything.<br />
**A broad range of topics is covered which is good, but there doesn't seem to be a logical structure to it - things don't lead on from each other.<br />
**The links to further external resources are a very good idea, and there are a lot of them, which is good and makes it easy to find out more and get a deeper understanding. Including these links also makes the page itself less crowded and helps keep a good overview.<br />
**The mere use of bullet points in most parts does keep things simple and clear, but also partly gives an impression of lack of depth. Certain points could be explained in a little bit more detail.<br />
**The table that is used for Screening Strategies is an efficient way of showing the data, though I don't quite understand what the "maternal age" screening procedure is, and how that can have a detection rate? I assume it relates to the fact that older mothers have a higher risk of bearing Down Syndrome children, but what exactly is the screening procedure?<br />
**Though the terms are explained in "detection using tandem nucleotide repeats", the section is still too technical. It doesn't explain why this technique allows the detection of the trisomy 21. For somebody who isn't familiar with genetics, it is very hard to understand. I am familiar with genetics, but the sentence "Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by ..." doesn't quite make sense to me - how can the sequences be amplified ON the maternal plasma?<br />
**Listing the screening by country is a good idea, but then should contain more than just information for 1 country.<br />
**Generally, there is a curious mix of very well explained terms and sections, and sections that still seem incomplete.<br />
----<br />
--[[User:Z3389343|z3389343]] 11:09, 22 September 2011 (EST)<br />
----<br />
===Lab 8 Assessment===<br />
Peer Assessment<br />
----<br />
--[[User:Z3389343|z3389343]] 11:15, 29 September 2011 (EST)<br />
----<br />
--[[User:Z3389343|z3389343]] 11:12, 6 October 2011 (EST)<br />
----<br />
===Lab 10 Assessment===<br />
*Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.<br />
The cytomegalovirus is known to cause hearing loss in a fetus whose mother is newly infected.<br />
*Identify 3 factors that contribute to poor neonatal drainage of the middle ear.<br />
The fluid normally drains out of the middle ear through the eustachian tubes. In neonates, the eustachian tubes are at a more horizontal level than in the adult, which leads to poorer drainage of the middle ear. Furthermore, the eustachian tubes in a neonate are smaller than in the adult structure, which leads them to be obstructed more easily, which can also obstruct fluid drainage.<br />
Another factor that has been associated to poor drainage of the middle ear is a cleft palate.<br />
*Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)<br />
The Axenfeld-Rieger syndrome has been associated with sensorineural hearing loss. http://www.omim.org/entry/602482?search=hearing%20development&highlight=development%20hearing<br />
<br />
==Peer Assessment==<br />
===Group 1 - Turner Syndrome===<br />
*'''Introduction''': The second paragraph of the introduction partly observes poor sentence structure, and in general needs a little bit more clarification. Also, I wouldn't necessarily include that information in the introduction, but put it under a different heading, etiology maybe? The following paragraph is good, just watch out with this sentence: "Each person who has turner syndrome all vary" - that doesn't quite make sense. Each person varies, or people with TS all vary...<br />
*'''Epidemiology''': This sentence really doesn't make sense to me: "Whereby, the maternal X is retained in two-thirds of women and the paternal X in the remainder." Furthermore, the whole paragraph needs editing in terms of sentence structure. The content is good, though could do with slightly more explanation.<br />
*The table with the common abnormalities is good, but in a slightly random place.<br />
*None of these first sections include links to the glossary. Explaining some of the terms in more detail could easily be achieved by linking them to the glossary.<br />
*'''Etiology''': Be careful when saying meiosis creates genetic diversity. Yes, meiosis creates diversity by shuffling existing alleles and producing new combinations, but the underlying mechanism, which is the main drive for genetic diversity, is mutation because that is what creates new alleles. (I'm just saying this because my lecturer in genetics was very keen on making us understand this difference!) Other than that, excellent explanation of how the genotype of Turner Syndrome occurs. Considering some of the genetic component was also explained under epidemiology, it would be useful to relate this information to what has already previously been mentionned.<br />
*'''Clinical Manifestations''': Poor. Referencing not done properly, no explanations, a simple list really tells hardly anything about the manifestations. Linking them to articles is useful, but not doing anything else makes the whole exercise of creating a page dedicated to a disease pointless if there won't actually be any descriptions or explanations.<br />
*'''Diagnostic Procedures''': Very well explained, good use of diagrams and figures to illustrate the text.<br />
*'''Treatment''': Links to the glossary would be good. Content is good, but the referencing isn't done properly, and some figures would be nice to illustrate things, it looks a little bit dry as such a long blurb of text.<br />
*'''Current research''': Looks fine to me<br />
*'''Future research''': Good idea!<br />
*'''Glossary''': Could be more extensive, mainly because some sections do not contain any links to the glossary.<br />
*'''References''': Needs fixing. it appears as though it hasn't been done right a single time... (ie one and the same paper occurs multiple times in the list)<br />
*General: There are obvious quality differences between the different sections, which is a shame. Parts are done really well, others not so much. The content and subsections would be fine if they all had the same standard as the well-written ones.<br />
<br />
===Group 2 - DiGeorge Syndrome===<br />
*'''Introduction''': Good in general. Last paragraph needs a slight revision in sentence structure. "The clinical manifestations of the chromosome 22 deletion are significant and can lead to poor quality" - significant in what way? As in they have a big impact? And also, poor quality of what? Life?<br />
*'''Historical Background''' : Very detailed, which is nice. The layout isn't quite 100% consistent, which should be easily fixed. Some findings could do with further explanations to show how this lead to progress. Also, some terms should be linked to the glossary, or in some cases, a mention that subsequent paragraphs will provide more detail.<br />
*'''Epidemiology''': Seems fine to me, though a figure would be nice to break up the text.<br />
*'''Etiology''': Links to glossary needed. This part contains many technical terms that aren't explained. Also, is it known why this region is specially prone to rearrangements?<br />
*'''Pathogenesis''': Seems to repeat what was said in etiology, but in more detail. Well written and explained.<br />
*'''Diagnosis''': There's a typo in the title - Dianostic instead of Diagnostic. You might want to split your table into prenatal and postnatal, as otherwise it is a bit confusing to read "ultrasound" as a diagnostic tool. It does become obvious very quickly that it is prenatal, but just for clarity's sake, splitting the table could help, especially as you mix pre- and postnatal tools throughout the table. Also, just be careful about using capitals - in the beginning you say BACS, and later you say BACs. BACs is the plural of BAC, which is what Bacterial Artificial Chromosome stands for, not BACS. Your explanations in this part of the table are quite technical - you might want to explain more terms in the glossary at least.<br />
*'''Clinical Manifestations''': Very thorough and detailed, which is good. I like the table, but including some more figures might help break up the long bits of text.<br />
*'''Treatment''': Also quite thorough, well explained.<br />
*'''Current and Future Research''': Very good and detailed, well explained. Maybe include headings for the different sections, so it's easier to see what each is talking about?<br />
*'''Glossary''': More terms need explanations.<br />
*'''References''': Seem fine in general, though there are a few links that probably should be cited differently. Also, some references link to emptiness?<br />
*General: All the tables are slightly differently formatted, you might want to get that more uniform.<br />
<br />
===Group 3 - Klinefelter's Syndrome===<br />
*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?<br />
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.<br />
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!<br />
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?<br />
The genetics part is good though.<br />
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!<br />
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?<br />
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.<br />
*'''Management''': Looks good.<br />
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.<br />
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?<br />
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.<br />
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.<br />
<br />
===Group 4 - Huntington's Disease===<br />
*'''Intro''': Content is fine, but revise some of your sentences - they are a bit long winded and hard to follow.<br />
*'''History''': Looks good.<br />
*'''Epidemiology''': Nice detail.<br />
*'''Genetics''': Your first sentence doesn't quite make sense. That is not an adequate explanation of autosomal-dominant. Also, in case both parents have the disease, the likelihood of the offspring having the disease is still not 100% - it's 75%.<br />
Also, are you sure there is a mutation that causes the repeat to expand? Repeats in general are susceptible to mutations, especially expansions - that is different from there being another mutation elsewhere in the genome causing the repeat to expand. More terms need to be explained in the glossary. Nice hand-drawn figure though.<br />
There's a reasonable amount of information why the disease tends to be inherited in an anticipating pattern, so you could possibly add that information.<br />
*'''Molecular Mechanisms & Pathogenesis''': Nice detail. Why are some terms in bold and coloured? More terms need to be explained in the glossary.<br />
*'''Clinical Manifestations''': Good.<br />
*'''Diagnostic Tests''': Otherwise fine, but you could briefly mention which genetic tests can be used to diagnose the test genetically.<br />
*'''Video of Huntington's disease patient''': Why is this the main heading for this section? Doesn't quite make sense. Otherwise, the section is good, I like the use of figures to break up the text.<br />
*'''Treatment''': Nicely comprehensive. Rather few explanations in text form though, maybe expand on this a little bit more?<br />
*'''Current/Future Research''': Your "Culling out complex traits" figure doesn't have any explanation on the project page. Also, what exactly does it contribute, but a picture? It seems a bit redundant. Otherwise, nice detail.<br />
*'''Glossary''': Looks good, but some more terms still need explaining.<br />
*'''References''': Needs fixing, some papers appear multiple times, and some references lead to emptiness.<br />
<br />
===Group 5 - Fragile X Syndrome===<br />
*'''Introduction''': Concise and to the point.<br />
*'''History''': 1977... revise this sentence, I don't quite understand it. Generally, the explanations about the different discoveries could be longer and explain more how this lead to progress with regards to FXS.<br />
*'''Epidemiology''': All of the sudden you talk about "other populations" - which was the population you were initially referring to? Also, when you bullet-point the studies about the different populations, it would be good including a reference to each study.<br />
*'''Screening/Population testing''': Looks fine.<br />
*'''Etiology''': Generally well explained, though your last paragraph remains rather technical. You also sometimes use very long sentences - try to break those down, that'll make it easier to follow the argument. None of your terms seem to be explained in the glossary, and I doubt that anyone who hasn't done somewhat advanced genetics will understand the stuff relating to the RICS complex, the dicer enzyme and mRNA and miRNA regulation. Otherwise, nice depth and detail.<br />
*'''Development''': Well explained, good use of subheadings.<br />
*'''Signs and Symptoms''': Also well explained, good use of subheadings.<br />
*'''Diagnosis''': Too short. What about non-genetic diagnosis?<br />
*'''Treatment''': You jump in with mGluR5 treatment without having previously mentioned that this is affected by the syndrome. Mention it somewhere earlier, so it makes more sense that it needs to be treated?<br />
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?<br />
*'''Glossary''': Too short, more terms need to be explained.<br />
*'''References''': The links probably need fixing. Also, a few articles seem to appear a couple of times in the list, but in general it looks fine.<br />
*General: I feel like you mainly focus on the behavioural/cognitive aspects of the disease. Is there nothing more physiologicall to it? Otherwise, well organised, but maybe include a few more figures, as most of the page appears to be text?<br />
<br />
===Group 6 - Tetralogy of Fallot===<br />
*'''Intro''': What's a tet spell?<br />
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.<br />
*'''Edidemiology''': Looks fine<br />
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.<br />
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).<br />
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.<br />
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.<br />
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.<br />
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?<br />
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.<br />
*'''Glossary''': A bit poor. More technical terms need to be explained.<br />
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!<br />
<br />
===Group 7 - Angelman Syndrome===<br />
*'''Introduction''': brief and to the point.<br />
*'''History''': Very well explained, but references have been forgotten? Also, you mention two dates in the summary table, 1980 & 1982, that you don't seem to explain previously.<br />
*'''Epidemiology''': Looks a little bit bare. If there simply is not much information about it, I wouldn't split it in three sections with each only containing a sentence, but rather write one short paragraph.<br />
*'''Aetiology''': I assume the UBE3A gene lies within the 15q11.2-q13 region? You might want to specify that. Also, some terms should be linked to the glossary.<br />
*'''Pathogenesis''': Watch out with your terminology - you say "its function is vague" - its function most likely isn't vague, but it is only vaguely known. Subtle, but important difference. Why do you mention LTP? Is LTP affected in AS? Otherwise, impressive detail in the mechanisms, well explained.<br />
Not quite sure it makes sense to have the "animal models" subheading under pathogenesis. Maybe have a separate section, entitled, animal models used in the study of AS?<br />
I'd also suggest having pathophysiology as a brief, but separate section from pathogenesis, and not have it as a subsection.<br />
*'''Signs and Symptoms''': Not quite sure what the table is for? Having a table combined with text with subheadings seems a bit odd. The text is well explained. (Just correct obesity, not obeseness.)<br />
*'''Complications''': A bit brief and out of the blue. How does it link in with the rest? Maybe include in under another section instead of have it as its own.<br />
*'''Diagnosis''': Prenatal diagnosis looks good, very detailed. Just watch out with the chorionic villus sampling, not chronic villus sampling ;)<br />
Postnatal: Revise your first sentence, doesn't quite make sense. Also, it seems a bit brief, maybe add a bit more detail?<br />
Differential Looks fine.<br />
*'''Related Diseases''': Might make sense to combine this with differential diagnosis? Also, considering pretty much exactly the same region is affected in PWS as in AS, you might want to explain more how this still leads to two separate syndromes.<br />
*'''Treatment & Management''': Needs a bit more detail.<br />
*'''Prognosis''': The information provided seems a bit random, thus needs a bit more explanations and how it relates to everything else.<br />
*'''Genetic counseling''': No explanations provided, simple table. How are people supposed to understand this?<br />
*'''Current and Future Research''': Fine.<br />
*'''Glossary''': (Your definition of an allele is not quite right.) Otherwise looks good, though some more terms need explanations.<br />
*'''References''': The links probably need fixing, and some papers appear several times in the list.<br />
<br />
===Group 9 - Williams Syndrome===<br />
*'''Intro''': More info about the syndrome itself needed. Add a picture if you can? The text alone is a bit dry.<br />
*'''History''': ... 1952 is really not early. I'd call it a rather new syndrome if that's when it was discovered..? Otherwise, lots of info and references, which is good.<br />
*'''Genetic factors and Etiology''': Looks good.<br />
*'''Diagnosis''': Seems fine.<br />
*'''Epidemiology''': Not sure it makes sense to have management and treatment under epidemiology? Content seems fine, though is very text-heavy, maybe find a figure to break it up?<br />
*'''Phenotype''': I like the table. Gives an easy overview.<br />
*'''Cardiac Conditions''': Good content. I assume the "other problems" section is still under construction?<br />
*'''Genitourinary Conditions''': Content seems fine, but it's very text heavy, this really needs to be broken up somehow. Possibly use a table, or include more figures.<br />
*'''Endocrine''': Endocrine what? Conditions? That title is a bit odd. Otherwise, looks good. How come the thyroid section doesn't have a reference?<br />
*'''Other Associated Medical Conditions''': Good content, I like the table.<br />
*'''Cognitive, Behavioural and Neurological Phenotype''': Very impressive amount of (really interesting) information, which however currently mainly consists of text. Some more figures will help break that down a bit. (Watch out with the spatial cognition part - the title is spelled correctly, but within the text it's all "spacial".) Otherwise, very well done!<br />
*'''Structural Differences in the Brain''': Not quite sure it makes sense to have this section here - put it before the cognitive phenotype section, instead after? Content is very good.<br />
*'''Specialised Facilities and Supportive Associations''': Interesting idea. Not quite sure it's needed cause I think we're supposed to focus on the science, but at the same time I don't see why not include it. Though your formatting makes it a very long section - I'd keep it more brief.<br />
*'''Current research and developments''': A little bit too brief. You could expand a little bit more on what is being done. The links are good, but maybe give a few more examples of recent papers and reviews.<br />
*'''Glossary''': Poor. MANY more terms need explanations.<br />
*'''References''': Looks fine in general, though the link might need fixing, and also one reference leads to emptiness?<br />
*General: From the conditions sections onwards I'm not quite sure the sections and different titles you have chosen make sense, it seems a bit confusing. Maybe rethink that and try and come up with a more clear structure? Also, you need to make your structuring and how you split up a section into subsections more uniform.<br />
Overall though, you cover an impressive spectrum of information. Well done!<br />
<br />
===Group 10 - Duchenne Muscular Dystrophy===<br />
*'''Intro''': Fine<br />
*'''History''': Nicely detailed, but missing a timeline.<br />
*'''Epidemiology''': Seems fine, though you might wanna mention that the daughter of an affected male will automatically become a carrier. Or do males generally not survive til reproductive age?<br />
*'''Aetiology - Genetics''': Could do with a little bit more detail on the actual genetics/mutations, how they occur, if it is known why they occur, what effect it has.<br />
*'''Pathogenesis''': Content seems fine, could do with a figure?<br />
*'''General Signs and Symptoms of Duchenne’s Muscular Dystrophy''': Not sure I'd give this it's own subsection - maybe put it under the next one?<br />
*'''Clinical manifestations and complications''': Fine<br />
*'''Diagnosis''': Clinical Diagnosis is a bit short?<br />
*'''Treatment: Current and Future Prospects''': Poor. Treatment needs expansion. The table doesn't give much detail.<br />
*Where's the current research section? Surely you could use at least some bits of the future prospects for treatment for this.<br />
*'''Glossary''': Poor. More terms need explanations.<br />
*General: The content is rather superficial. It is a very small page? Surely there must be more information available. Also, more figures are needed.<br />
<br />
===Group 11 - Cleft Palate and Lip===<br />
*'''Introduction''': Too short. Also, how come there are no references? How about starting with a brief anatomical description?<br />
*'''History''': No reference for the first paragraph? I like the idea of mentioning Plato, but could you then also expand a little bit more on his thoughts? Also, what was the explanation offered by Philippe Frederick Blandin?<br />
*'''Timeline''': Looks good to me, though some terms should be explained in the glossary.<br />
*'''Diagnosis''': I'm not sure I'd make this follow on immediately from the Timeline. I would put this section between Types of Cleft Palate/Lip & Pathophysiology, maybe? While you do talk about the technical difficulties just before the Cleft Soft Palate Detection part, but considering you start a new subsection, it's confusing to keep talking as if it was the same paragraph. Maybe say "the technical difficulties mentionned above" instead? An explanation in the glossary of what a cleft soft palate actually is, is definately needed! The Cleft Hard Palate section is very well done.<br />
*'''Syndromes and Anomalies associated with cleft''': Looks fine.<br />
*'''Development''': Under construction? or is there meant to be no text, and you're simply splitting this section into the two subsections? If yes, you might want to make that clearer.<br />
*'''Aetiology''': This part is slightly technical and could do with some more detailed explanations. It doesn't feel like a coherent section.<br />
*'''Developmental Staging''': Well explained.<br />
*'''Types of Cleft Palate/Lip''': Looks fine. Though the "algorhythm for repair..." figure seems to be in a slightly random place..? How does it relate to this section (or the next)?<br />
*'''Pathophysiology''': The cranio-facial development pathway is a very complex process. Since the several points of development at which “Clefting” might occur is based on the condition and the wide range of its phonotypical expression. Make this one sentence? You start talking about neural crest cells quite out of the blue. Has there been any mention of them before? It's quite confusing to have them added into the story without having previously told why. The first two paragraphs under the table lack references? This part repeats what has been partly said before, but adds more physiological detail to it. I'd find it more logical to combine the different aspects to give one, more complete picture.<br />
*'''Genetic configuration''': Very poor language/sentence structure. Where are the references? Putting womb and external environment together does make sense, but you might want to explain in a sentence why.<br />
*'''Neuroembryology and functional anatomy of craniofacial clefts''': Excellent explanation, though some terms should be explained in the glossary. Why are some words in bold? Again, this sort of repeats previous information, again with more detail from a different point of view, apparently unrelated to what's been told before, as this section doesn't follow the previous sections?<br />
*'''Treatment''': Can you explain the different techniques a little bit more, instead of just having bullet points? The figures are really nice, but don't illustrate all of the techniques mentioned.<br />
*'''Problems associated with Cleft Palate''': Mere list with bullet points isn't enough, more explanations needed.<br />
*'''Current and Future Research''': Very poor. There must be more than 3 articles?<br />
*'''Glossary''': Poor. Many more terms need explanations.<br />
*'''References''': Need fixing. The same article appears lots of times in the list. Watch out with your german references... the fact that you misspell the german makes me wonder whether you could have actually read the papers? In case you're citing a reference cited within the reference you've read, there usually is a special way of doing it.<br />
*General: Your sections are really random and don't follow logically from one another. There is a lot of repetition of similar content in multiple different places, which is confusing. It is hard to keep an overview. Nevertheless, some of the sections are well done.<br />
<br />
==Group Project References==<br />
<br />
Current research: <ref>http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli</ref><br />
<br />
Mapping of frataxin gene: <ref>http://www.nature.com/nature/journal/v334/n6179/abs/334248a0.html</ref><br />
<br />
Genetics: <ref>http://www.nejm.org/doi/full/10.1056/NEJM199610173351601#t=articleBackground</ref><br />
<br />
<ref><pubmed>8596916</pubmed></ref><br />
<br />
<ref><pubmed>11351269</pubmed></ref><br />
<br />
<ref><pubmed>11269509</pubmed></ref><br />
<br />
check Jiralerspong S, Liu Y, Montermini L et al. (1997). Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 4: 103–113.<br />
for developmental genetics<br />
<br />
----<br />
<br />
<br />
==Group Project Work==<br />
<br />
<br />
===Genetic Component===<br />
<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location on chromosome was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a '''linkage study''' for the mapping. Subsequent studies further refined its location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA '''triplet repeat''' in the first '''intron''' of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus '''heterozygous''' carriers of the repeat are clinically normal. Most FRDA patients are '''homozygous''' for a repeat expansion, although there are some rare cases of '''heterozygous''' patients who have a repeat expansion on one allele and a missense or nonsense point mutation on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
====Evolution====<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 carriers in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximatively 17% of clinically normal repeats consist of repeats of longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a '''founder event'''. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In same cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
====Genetic instability====<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA '''replication''', one strand of the DNA template may loop out and become displaced, alternatively, '''DNA polymerase''' might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
====Consequences of the mutation====<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that splicing of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that mRNA levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are purines while T (thymine) and C (cytosine) are pyrimidines. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to gene silencing. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein that can bind iron and is thought to be involved in the mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
<br />
''Add more about histone modifications''<br />
<br />
===Glossary===<br />
<br />
<br />
----<br />
<br />
===Inheritance===<br />
<br />
GAA repeat is unstable - leads to anticipating pattern of inheritance of GAA repeat<br />
<br />
===Genetic Expression===<br />
<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embroys <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the periventricular zone, the cortical plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
<br />
----<br />
<br />
<br />
Notes:<br />
<br />
Cosse´e M, Schmitt M, Campuzano V et al. (1997). Evolution<br />
of the Friedreich’s ataxia trinucleotide repeat expansion:<br />
founder effect and premutations. Proc Natl Acad Sci U S A<br />
94: 7452–7457.<br />
<br />
the longer the repeat - the more susceptible it is to mutations --> repeat instability --> replication slippage<br />
from normal long repeat can get to pathological repeat within one single generation<br />
<br />
<br />
transcriptional consequences of GAA repeat:<br />
check The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.<br />
and Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities<br />
<br />
<br />
Rename "consequences of mutation" frataxin gene silencing? put it in somewhere else?<br />
<br />
Check Prenatal Diagnosis 1995 for map of markers around the frataxin gene<br />
<br />
==References==<br />
<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=776942011 Group Project 82011-10-12T23:48:06Z<p>Z3389343: /* Treatment */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
{|align="right"<br />
|-<br />
|[[File:GAA Frequency in FRDA.jpg|370px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|-<br />
|[[File:Symptoms and signs in FRDA patients.jpg|370px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
'''Distribution'''<br />
<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']]. More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']], which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']], and thus preventing hypoacetylation<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
Histone deacetylase inhibitors (HDACI) have been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI returned the levels of genetic expression of the frataxin gene, responsible for the production of the frataxin protein, to normal. HDACI is able to cross the blood brain barrier and acetylate histones, furthermore tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebenone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebenone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebenone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
<br />
* [[Cardiac Embryology]] - Development of heart.<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
* [[Molecular Development - Genetics]] - The genetics and molecular mechanisms of development.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Neural - Cerebellum Development]] - This page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Acetylation''' - The process of adding an acetyl group into a compound. Acetylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Deacetylation''' - The removal of an acetyl group to a compound.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypoacetylation''' - Less acetylated than in normal circumstances.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Methylation''' - Enzymatic transfer of methyl groups to biological molecules, such as RNA and DNA. Methylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=776832011 Group Project 82011-10-12T23:38:24Z<p>Z3389343: /* Related Links */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
{|align="right"<br />
|-<br />
|[[File:GAA Frequency in FRDA.jpg|370px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|-<br />
|[[File:Symptoms and signs in FRDA patients.jpg|370px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
'''Distribution'''<br />
<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']]. More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']], which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']], and thus preventing hypoacetylation<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebenone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebenone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebenone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
<br />
* [[Cardiac Embryology]] - Development of heart.<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
* [[Molecular Development - Genetics]] - The genetics and molecular mechanisms of development.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Neural - Cerebellum Development]] - This page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Acetylation''' - The process of adding an acetyl group into a compound. Acetylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Deacetylation''' - The removal of an acetyl group to a compound.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypoacetylation''' - Less acetylated than in normal circumstances.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Methylation''' - Enzymatic transfer of methyl groups to biological molecules, such as RNA and DNA. Methylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=774352011 Group Project 82011-10-12T12:17:02Z<p>Z3389343: /* Glossary */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']]. More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']], which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']], and thus preventing hypoacetylation<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebenone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebenone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebenone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Acetylation''' - The process of adding an acetyl group into a compound. Acetylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Deacetylation''' - The removal of an acetyl group to a compound.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypoacetylation''' - Less acetylated than in normal circumstances.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Methylation''' - Enzymatic transfer of methyl groups to biological molecules, such as RNA and DNA. Methylation of DNA is associated with the regulation of gene expression and with epigenetic phenomena such as imprinting.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=774292011 Group Project 82011-10-12T12:10:15Z<p>Z3389343: /* Current Research */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
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Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
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Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
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'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
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{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
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===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
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This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
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Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
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Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
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<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
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The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
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<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
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<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
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<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
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'''The Corticospinal Tract'''<br />
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This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
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Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
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The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']]. More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']], which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']], and thus preventing hypoacetylation<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebenone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebenone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebenone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
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* [[Cardiac Embryology]] - Development of heart<br />
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* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
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==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
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Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
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Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
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Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
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Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
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Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
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Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
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Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
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Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
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Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
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Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
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==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
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'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
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'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
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'''Apoptosis''' - Programmed cell death.<br />
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'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
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'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
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'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
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'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
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'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
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'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
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'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
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'''CNS''' - Central Nervous System.<br />
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'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
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'''Cortical''' - Of or relating to the cortex.<br />
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'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
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'''DNA''' - Deoxyribonucleic Acid.<br />
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'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
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'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
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'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
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'''DRG''' - Dorsal Root Ganglion.<br />
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'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
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'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
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'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
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'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
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'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
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'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
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'''FRDA''' - Friedreich's Ataxia.<br />
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'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
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'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
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'''Gene silencing''' - Inhibition of the gene expression.<br />
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'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
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'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
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'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
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'''Histone''' - A protein around which DNA coils to form chromatin.<br />
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'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
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'''Heterozygous''' - Possessing two different variants of a gene.<br />
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'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
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'''Homozygous''' - Possessing two identical variants of a gene.<br />
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'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
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'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
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'''Hypotonia''' - Decrease in muscle tone. <br />
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'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
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'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
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'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
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'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
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'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
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'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
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'''Neurological''' - Pertaining to the nervous system or nerves.<br />
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'''Neuron''' - The excitable cell of the nervous system. <br />
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'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
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'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
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'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
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'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
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'''Pes cavus''' - Feet with abnormally high arches.<br />
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'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
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'''Phenotype''' - Traits or characteristics that are observable externally.<br />
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'''Pneumonia''' - Inflammatory condition of the lungs. <br />
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'''PNS''' - Peripheral Nervous System.<br />
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'''Point mutation''' - A mutation affecting a single nucleotide.<br />
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'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
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'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
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'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
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'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
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'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
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'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
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'''Replication''' - The process whereby DNA is duplicated.<br />
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'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
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'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
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'''Sepsis''' - Infection of the blood, generally bacterial.<br />
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'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
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'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
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'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
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'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
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'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
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==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=774262011 Group Project 82011-10-12T12:08:11Z<p>Z3389343: /* Treatment */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']]. More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']], which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']], and thus preventing hypoacetylation<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebenone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=774202011 Group Project 82011-10-12T11:59:29Z<p>Z3389343: /* Treatment */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of '''FRDA''', including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of '''FRDA'''. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
The repeat expansion seen in the frataxin gene in FRDA patients has been observed to be accompanied with abnormal chromatin formation, which includes abnormal [[#Glossary | '''histone''']] [[#Glossary |'''methylation''']] and [[#Glossary |'''acetylation''']] . More specifically, histones H3 and H4 are known to be [[#Glossary |'''hypoacetylated''']] , which is now being targeted through histone deacetylase inhibitors (HDACI), stopping [[#Glossary |'''deacetylation''']] , and thus preventing hypoacetylation.<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of '''frataxin''' to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of '''FRDA'''. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of '''frataxin'''. HDACI is able to cross the blood brain barrier and acetylate [[#Glossary | '''histones''']], however tests with KIKI mouse models (FRDA mouse models) have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of '''FRDA'''.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays''''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebnone delays '''FRDA''' in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. '''Frataxin''' levels appear to affect mitochondrial function and therefore slow the progression of '''FRDA'''. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=773572011 Group Project 82011-10-12T11:02:24Z<p>Z3389343: /* Treatment */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of '''FRDA''', including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of '''FRDA'''. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of '''frataxin''' to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of '''FRDA'''. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of '''frataxin'''. HDACI is able to cross the blood brain barrier and acetylate [[#Glossary | '''histones''']], however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of '''FRDA'''.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays''''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebnone delays '''FRDA''' in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. '''Frataxin''' levels appear to affect mitochondrial function and therefore slow the progression of '''FRDA'''. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=773552011 Group Project 82011-10-12T11:00:22Z<p>Z3389343: /* Treatment */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of '''FRDA''', including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of '''FRDA'''. Due to the insufficient frataxin levels in FRDA, iron is transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since frataxin deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of '''frataxin'''<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of '''frataxin''' to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of '''FRDA'''. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of '''frataxin'''. HDACI is able to cross the blood brain barrier and acetylate [[#Glossary | '''histones''']], however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of '''FRDA'''.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays''''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebnone delays '''FRDA''' in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. '''Frataxin''' levels appear to affect mitochondrial function and therefore slow the progression of '''FRDA'''. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=773472011 Group Project 82011-10-12T10:55:00Z<p>Z3389343: /* Glossary */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of '''FRDA''', including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of '''FRDA'''. '''FRDA''' causes iron to be transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since [[#Glossary | '''frataxin''']] deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of '''frataxin'''<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of '''frataxin''' to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of '''FRDA'''. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of '''frataxin'''. HDACI is able to cross the blood brain barrier and acetylate [[#Glossary | '''histones''']], however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of '''FRDA'''.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays''''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebnone delays '''FRDA''' in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. '''Frataxin''' levels appear to affect mitochondrial function and therefore slow the progression of '''FRDA'''. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - An iron-sulphur protein involved in iron homeostasis.<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities.<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart.<br />
<br />
'''Chelation''' - Chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions. ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid.<br />
<br />
'''DNA marker''' - A gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' - Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current).<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - Exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=773392011 Group Project 82011-10-12T10:50:36Z<p>Z3389343: /* Diagnostic Tools */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in '''Genetic Testing'''.<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of '''FRDA''', including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of '''FRDA'''. '''FRDA''' causes iron to be transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since [[#Glossary | '''frataxin''']] deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of '''frataxin'''<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of '''frataxin''' to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of '''FRDA'''. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of '''frataxin'''. HDACI is able to cross the blood brain barrier and acetylate [[#Glossary | '''histones''']], however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of '''FRDA'''.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays''''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Treatment with idebnone delays '''FRDA''' in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. '''Frataxin''' levels appear to affect mitochondrial function and therefore slow the progression of '''FRDA'''. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=77165Talk:2011 Group Project 82011-10-12T07:00:59Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
oki dokes people, it's all in there - the table and the picture of the gene!<br />
after some thinking, I came to the conclusion that I don't think it makes sense to have the picture of the protein in the treatment section - none of it talks about the protein itself. I guess we could put it into the genetics bit after all? what do you think?<br />
and yes to meeting tomorrow after the lecture.<br />
<br />
I think the table is great! definitely add it in! do we have a backup plan if you dont get permission for the chromosome pic?<br />
should we all meet in the break after the lecture??<br />
<br />
z3294943<br />
<br />
<br />
Right, what do you think about the table? That enough detail? Also, I didn't put any more information into the third row on purpose - what it is about is literally what it says on the "area of research". And as it is only one paper, which is a very long review, I don't see the point in giving more info. What do you think?<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=771642011 Group Project 82011-10-12T06:58:43Z<p>Z3389343: /* Current Research */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. FRDA causes iron to be transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since [[#Glossary | '''frataxin''']] deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays'FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
Treatment with idebnone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:20%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:45%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| This publication reviews different current and prospective treatment possibilities and assesses their respective advantages and disadvantages.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=771582011 Group Project 82011-10-12T06:45:16Z<p>Z3389343: /* Genetic Component */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref>.<br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
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<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
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<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
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<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
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{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
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'''Iron-chelation'''<br />
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Treating with iron chelators is very effective in delaying the progress of FRDA. FRDA causes iron to be transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since [[#Glossary | '''frataxin''']] deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
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<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
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<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
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<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
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Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
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'''Antioxidants'''<br />
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Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
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*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays'FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
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Treatment with idebnone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
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<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:<br />
:A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
:Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
:Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
:Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
:New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
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The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
:In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
:Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
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Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
:Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
:Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
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Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
:Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
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==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
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* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
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* [[Cardiac Embryology]] - Development of heart<br />
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* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
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==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
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Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
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Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
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Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
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Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
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Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
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Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
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Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
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Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
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Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
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Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
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==Glossary==<br />
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[[#Introduction | '''Back to top''']]<br />
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'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
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'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
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'''Apoptosis''' - Programmed cell death.<br />
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'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
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'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
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'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
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'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
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'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
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'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
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'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
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'''CNS''' - Central Nervous System.<br />
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'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
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'''Cortical''' - Of or relating to the cortex.<br />
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'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
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'''DNA''' - Deoxyribonucleic Acid <br />
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'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
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'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
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'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
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'''DRG''' -Dorsal Root Ganglion.<br />
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'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
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'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
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'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
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'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
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'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
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'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
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'''FRDA''' - Friedreich's Ataxia.<br />
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'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
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'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
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'''Gene silencing''' - Inhibition of the gene expression.<br />
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'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
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'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
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'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
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'''Histone''' - A protein around which DNA coils to form chromatin.<br />
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'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
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'''Heterozygous''' - Possessing two different variants of a gene.<br />
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'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
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'''Homozygous''' - Possessing two identical variants of a gene.<br />
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'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
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'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
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'''Hypotonia''' - Decrease in muscle tone. <br />
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'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
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'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
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'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
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'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
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'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
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'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
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'''Neurological''' - Pertaining to the nervous system or nerves.<br />
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'''Neuron''' - The excitable cell of the nervous system. <br />
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'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
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'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
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'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
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'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
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'''Pes cavus''' - Feet with abnormally high arches.<br />
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'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
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'''Phenotype''' - Traits or characteristics that are observable externally.<br />
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'''Pneumonia''' - Inflammatory condition of the lungs. <br />
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'''PNS''' - Peripheral Nervous System.<br />
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'''Point mutation''' - A mutation affecting a single nucleotide.<br />
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'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
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'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
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'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
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'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
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'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
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'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
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'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
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'''Replication''' - The process whereby DNA is duplicated.<br />
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'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
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'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
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'''Sepsis''' - Infection of the blood, generally bacterial.<br />
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'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
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'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
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'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
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'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
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'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
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==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=771572011 Group Project 82011-10-12T06:42:30Z<p>Z3389343: /* Treatment */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
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In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) is a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA, including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>:<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. FRDA causes iron to be transferred from the cytosol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since [[#Glossary | '''frataxin''']] deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cytosol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, iron-chelation has been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays'FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
Treatment with idebnone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:<br />
:A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
:Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
:Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
:Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
:New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
:In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
:Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
:Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
:Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
:Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=771552011 Group Project 82011-10-12T06:36:07Z<p>Z3389343: /* Genetic Component */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q11-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
<br />
{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. FRDA causes iron to be transferred from the cystol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since [[#Glossary | '''frataxin''']] deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cycstol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-chelation had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays'FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
Treatment with idebnone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:<br />
:A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
:Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
:Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
:Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
:New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
:In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
:Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
:Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
:Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
:Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=771542011 Group Project 82011-10-12T06:32:40Z<p>Z3389343: /* Genetic Component */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
[[File:Location of the frataxin gene on chromosome 9.jpg|350px|thumb|Location of the frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
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{|align="left"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
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The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
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<br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
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<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Friedreichs Ataxia (FRDA) a degenerative congenital disorder with no treatments available<ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. There are several therapies that may potentially be used to delay the progression of FRDA including<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|300px|thumb|Role of FXN Gene]]<br />
|}<br />
*Iron chelators<br />
* Histone deacetylase inhibitors(HDACI)<br />
* Antioxidant<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
Treating with iron chelators is very effective in delaying the progress of FRDA. FRDA causes iron to be transferred from the cystol into the mitochondria<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>, where it accumulates. Since [[#Glossary | '''frataxin''']] deficiency is linked to low levels of cystolic iron, iron supplements have potential to make up for the low levels of frataxin<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref>. The most effective chelators directly target mitochondrial iron, allowing iron levels in the cycstol to be maintained<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref>. This is clearly depicted from the role of the FXN gene image presenting the importance of the FXN gene in causing a cascade of effects within the mitochondria in regards to iron homoeostasis.<br />
<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-chelation had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|300px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
<br />
Histone deacetylase inhibitor (HDACI) has been proven to return levels of frataxin to normal in the nervous system and the heart<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>, which in turn delays the progression of FRDA. Therapeutic use of HDACI did not affect levels of genetic expression for the gene responsible for producing frataxin, FXN gene is the gene responsible for the production of frataxin. HDACI is able to cross the blood brain barrier and acetylate histones, however tests with KIKI mouse models have shown that this does not cause abnormal behaviour or pathological effects<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
Treatment of oxidative stress within mitochondria is possible through the administration of Idebenone or a combination of Coenzyme Q10 with Vitamin E in delaying the progress of FRDA.<br />
<br />
*Coenzyme Q10 with Vitamin E acts as an electron carrier and reduces oxidative stress<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. The combination of Coenzyme Q10 and Vitamin E normalises Mitochondrial ATP synthesis function, resulting in a decrease of oxidative damage to the mitochondria. Positive effects observed within skeletal and cardiac muscle are linked to decreased mitochondrial stress, which allows for the normal function of mitochondria which effective delays'FRDA<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
Treatment with idebnone delays FRDA in two ways<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Idebnone acts as an anti-oxidant, helping to prevent oxidative damage to the mitochondria. It also acts as an electron carrier and supports mitochondrial function. Frataxin levels appear to affect mitochondrial function and therefore slow the progression of FRDA. In ~50% of patients in trial, idebnone has successfully reduced the left ventricular mass by 20%<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:<br />
:A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
:Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
:Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
:Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
:New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
:In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
:Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
:Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
:Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
:Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Location_of_the_frataxin_gene_on_chromosome_9.jpg&diff=77150File:Location of the frataxin gene on chromosome 9.jpg2011-10-12T06:25:23Z<p>Z3389343: Cytogenetic Location: 9q21.11
Molecular Location on chromosome 9: base pairs 71,650,478 to 71,715,093
The FXN gene is located on the long (q) arm of chromosome 9 at position 21.11.
More precisely, the FXN gene is located from base pair 71,650,478 to base</p>
<hr />
<div>Cytogenetic Location: 9q21.11<br />
Molecular Location on chromosome 9: base pairs 71,650,478 to 71,715,093<br />
<br />
The FXN gene is located on the long (q) arm of chromosome 9 at position 21.11.<br />
More precisely, the FXN gene is located from base pair 71,650,478 to base pair 71,715,093 on chromosome 9.<br />
<br />
Reference: <br />
U.S. National Library of Health '''FXN Gene''' 2010. Retrieved October 12, 2011, from http://ghr.nlm.nih.gov/gene/FXN<br />
<br />
NLM Copyright Information<br />
Government information at NLM Web sites is in the public domain. Public domain information may be freely distributed and copied, but it is requested that in any subsequent use the National Library of Medicine (NLM) be given appropriate acknowledgement. When using NLM Web sites, you may encounter documents, illustrations, photographs, or other information resources contributed or licensed by private individuals, companies, or organizations that may be protected by U.S. and foreign copyright laws. Transmission or reproduction of protected items beyond that allowed by fair use as defined in the copyright laws requires the written permission of the copyright owners. Specific NLM Web sites containing protected information provide additional notification of conditions associated with its use.</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76947Talk:2011 Group Project 82011-10-11T11:28:54Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Right, what do you think about the table? That enough detail? Also, I didn't put any more information into the third row on purpose - what it is about is literally what it says on the "area of research". And as it is only one paper, which is a very long review, I don't see the point in giving more info. What do you think?<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:25%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:40%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
|<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
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<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
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<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
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<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76945Talk:2011 Group Project 82011-10-11T11:23:57Z<p>Z3389343: /* Collated Peer Review */</p>
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<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
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{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Right, how much more detail do you want me to give about the individual papers? I'll be honest, I can't be bothered reading more than the abstracts, and also I don't want to make the section super text heavy. And generally, my one sentence descriptions give you the nutshell information of what the article is about. We've got so much information about the related things all over our page - people can just read it there, or follow the link to the article. I don't see much point in giving more info than that. But if you guys really want me to, I shall try and be more elaborate.<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:25%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:40%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
|<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children.<br />
| The same evaluation criteria of FRDA are commonly used for both adults and children, even though the progression of the disease is different in younger ages. Therefore, further research needs to look at the progression of the different factors affected in children with FRDA.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Currently, there are several different measures for quantifying the progression of FRDA. Evaluating which one is the most accurate is important in order to increase clinically significant benefits for the patients.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76944Talk:2011 Group Project 82011-10-11T11:07:17Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Right, how much more detail do you want me to give about the individual papers? I'll be honest, I can't be bothered reading more than the abstracts, and also I don't want to make the section super text heavy. And generally, my one sentence descriptions give you the nutshell information of what the article is about. We've got so much information about the related things all over our page - people can just read it there, or follow the link to the article. I don't see much point in giving more info than that. But if you guys really want me to, I shall try and be more elaborate.<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| style="width:25%" |A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| style="width:35%" |The oxidative cell damage occuring in FRDA patients is thought to be due to increasing deposits of iron pools in mitochondria. Iron chelators are therefore being targeted in therapeutic treatment, and idebone has been used since the late 1990s <ref name="PMID10465173"><pubmed>10465173</pubmed></ref>. Current research is further trying to improve its therapeutic use.<br />
| style="width:40%" |A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
|<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children. These can differ to the ones used in adults, which nevertheless are commonly also used for younger ages.<br />
|<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
|<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| FRDA has a large impact on the quality of life of the people affected. Increased awareness of how the disease impacts the patients as well as improvements in genetic counseling can help both the counselors and affected individuals to be more prepared for the implications of the disease.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
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I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
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Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
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YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
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<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
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Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
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About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
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Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
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[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
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Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
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I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
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I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
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Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
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Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
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Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
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==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
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'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
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<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
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Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
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<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
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<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
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Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
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Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
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z3332178 =]<br />
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<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
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:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
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*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
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Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
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<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
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<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
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<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
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<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
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Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
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<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
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<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
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<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
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<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76941Talk:2011 Group Project 82011-10-11T10:38:02Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Right, how much more detail do you want me to give about the individual papers? I'll be honest, I can't be bothered reading more than the abstracts, and also I don't want to make the section super text heavy. And generally, my one sentence descriptions give you the nutshell information of what the article is about. We've got so much information about the related things all over our page - people can just read it there, or follow the link to the article. I don't see much point in giving more info than that. But if you guys really want me to, I shall try and be more elaborate.<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
|<br />
| A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
|<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children. These can differ to the ones used in adults, which nevertheless are commonly also used for younger ages.<br />
|<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
|<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
|<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
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I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
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[[File:Friedreich's Ataxia Pedigree.png]]<br />
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Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
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YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
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<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
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I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
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Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
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About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
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I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
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<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
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Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
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[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
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z3294943<br />
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Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
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z3294943<br />
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I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
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I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
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Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
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Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
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Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
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Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
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'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
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<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
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<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
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<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
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Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
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z3332178 =]<br />
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<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
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'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
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:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
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:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
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:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
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--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
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*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
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--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
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Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
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--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
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Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
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<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76936Talk:2011 Group Project 82011-10-11T09:06:49Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
|<br />
| A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
|<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children. These can differ to the ones used in adults, which nevertheless are commonly also used for younger ages.<br />
|<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
|<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
|<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
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<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
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'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
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<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
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'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
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'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
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<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
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<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
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<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
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<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=768482011 Group Project 82011-10-11T00:40:03Z<p>Z3389343: /* Pathogenesis */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
<br />
[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="left"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from '''FRDA''' patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for '''FRDA'''<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|330px|thumb|Role of FXN Gene]]<br />
|}<br />
<br />
Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the '''Frataxin''' deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential '''chelators''' are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-'''chelation''' had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated '''frataxin''' gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|330px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
Treatment of '''FRDA''' through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of '''fractin''' restoring to normal range within the nervous system and the heart, restoration of '''fractin''' levels was achieved where acetylisation of '''histones''' at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
<br />
<br />
Positive effects of '''fractin''' level restoration is signs of decrease in progression of '''FRDA'''. Therapeutic use of HDACI led to the normalization of the genetic expression of '''FRDA''' patients. Support of '''fractin''' level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to '''histones''' without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.<br />
<br />
*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of '''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:<br />
:A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
:Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
:Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
:Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
:New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
:In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
:Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
:Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
:Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
:Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
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'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
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'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
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'''DRG''' -Dorsal Root Ganglion.<br />
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'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76704Talk:2011 Group Project 82011-10-10T11:06:05Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''What it is about'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
|<br />
| A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
|<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages.<br />
|<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
|<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
|<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
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Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
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--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
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'''Group 8 Peer Review'''<br />
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• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
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• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
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• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
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• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
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• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
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• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
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• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
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• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
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• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
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--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
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*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
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*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
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*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
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*Pathogenesis: Love the image, very clear and concise.<br />
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*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
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*Clinical: Great content, and fantastic use of subheadings.<br />
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*Diagnosis: fantastic formatting for the tables. <br />
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*Treatments: Need an image of some sort here, but the information is very relative. <br />
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*Glossary: Needs to be placed before the reference list.<br />
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*References: Looks good, couldn’t find any mistakes.<br />
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*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
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--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
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'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
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Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
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Peer review of group 8: <br />
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*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
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'''Peer Review for Group 8'''<br />
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* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
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--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
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Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
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#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
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"What would improve this project...." <br />
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* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
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Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
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'''Group 8'''<br />
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History: Timeline could be more detailed.<br />
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Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
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Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
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Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
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Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
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Treatment: needs some pictures to balance out the text<br />
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Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
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--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
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•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
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•The timeline seems a little short however, is there anything else you can add after 1996?<br />
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•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
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•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
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•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
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•The references should be the last thing, underneath the glossary and external links <br />
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•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
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--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
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'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
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''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
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'''Group 8'''<br />
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*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
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'''Group 8'''<br />
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*The index should be on the left side<br />
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*Introduction: contend is fine, but could be a little more general<br />
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*History: is there mo important milestone after 1996?<br />
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*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
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*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
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*Pathogenesis: looks good<br />
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*Neuropathology: well done, very nice drawings<br />
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*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
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*Diagnosis: very well done<br />
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*Treatment: well done<br />
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*Research: should be more detailed contend<br />
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*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
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'''Group 8'''<br />
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*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
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--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
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===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
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--Z3389806 06:25, 27 September 2011 (EST)<br />
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'''Group 8 Critique'''<br />
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#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
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--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
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'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
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*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
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'''Friedreich's Ataxia'''<br />
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*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
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Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
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'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
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'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
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'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76699Talk:2011 Group Project 82011-10-10T10:49:17Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''Recent publications'''<br />
|-bgcolor="Azure"<br />
| A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective for FRDA.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of FRDA in order to allow accurate assessment and optimised treatment.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76698Talk:2011 Group Project 82011-10-10T10:47:34Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
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<br />
==Collated Peer Review==<br />
<br />
Hey guys, let me know what you think about this table for the current research, I'll try and add a third column explaining the areas of research a bit more, but at the mo I'm having trouble with my internet connection at home, and this library is only open til 10pm (and it's 10 to right now)...<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''Articles relating to that area of research:'''<br />
|-bgcolor="Azure"<br />
| A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
<br />
Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
<br />
Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
<br />
Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages.<br />
| In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment.<br />
| Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
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I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
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Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
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YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
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<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
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I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
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<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
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Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
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About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
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<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
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Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
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[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
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Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
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I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
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I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
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Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
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Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
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==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
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Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
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'''Peer Assessment'''<br />
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* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
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'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
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Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
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Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
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Current Research: Many references which is good. Once again, an image would be good.<br />
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Glossary and references are good, however place the glossary before the references. <br />
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Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
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<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
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<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
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Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
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Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
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z3332178 =]<br />
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'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
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'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
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:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
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:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
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:*Timeline could be better suited into a table.<br />
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:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
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:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
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--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
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*intro: maybe move the image into the history section<br />
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*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
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*student drawn image had no reference and is a little light on colour.<br />
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*external links were great <br />
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--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
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Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
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:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
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:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
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:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
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:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
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:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
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Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
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Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
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GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
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<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76697Talk:2011 Group Project 82011-10-10T10:43:11Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Hey guys, let me know what you think about this table for the current research:<br />
<br />
{|<br />
|-bgcolor="LightSeaGreen"<br />
| '''Area of research'''<br />
| '''Articles relating to that area of research:'''<br />
|-bgcolor="Azure"<br />
| A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA.<br />
| *A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
*Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
*Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
*Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Recent publication providing an overview of the current therapeutic perspective.<br />
| New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
|-bgcolor="Azure"<br />
| Evaluation criteria of FRDA in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages.<br />
| * In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
*Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
|-bgcolor="Azure"<br />
| Establishing norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment.<br />
| *Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
*Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
|-bgcolor="Azure"<br />
| Improvements in genetic counseling for FRDA patients.<br />
| Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
|}<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=766912011 Group Project 82011-10-10T10:21:56Z<p>Z3389343: /* Current Research */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
<br />
[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="right"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from '''FRDA''' patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for '''FRDA'''<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|330px|thumb|Role of FXN Gene]]<br />
|}<br />
<br />
Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the '''Frataxin''' deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential '''chelators''' are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-'''chelation''' had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated '''frataxin''' gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|330px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
Treatment of '''FRDA''' through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of '''fractin''' restoring to normal range within the nervous system and the heart, restoration of '''fractin''' levels was achieved where acetylisation of '''histones''' at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
<br />
<br />
Positive effects of '''fractin''' level restoration is signs of decrease in progression of '''FRDA'''. Therapeutic use of HDACI led to the normalization of the genetic expression of '''FRDA''' patients. Support of '''fractin''' level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to '''histones''' without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.<br />
<br />
*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of '''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA:<br />
:A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia (2010). <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
:Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study (2011). <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
:Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia (2011). <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
:Antioxidants and other pharmacological treatments for Friedreich ataxia (2009). <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
:New advances in the treatment of Friedreich ataxia: promisses and pitfalls (2011). <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
:In children with Friedreich ataxia, muscle and ataxia parameters are associated (2011). <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
:Neurophysiological evaluation in children with Friedreich's ataxia (2009). <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
:Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design (2010). <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
:Review: Evaluating the progression of Friedreich ataxia and its treatment (2009). <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
:Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling (2010). <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76684Talk:2011 Group Project 82011-10-10T09:54:40Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
<br />
{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Also, found an image of the frataxin gene on the chromosome that can be reused as long as its authors are being notified. I asked for permission, keep your fingers crossed we get it before thursday!<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76680Talk:2011 Group Project 82011-10-10T09:36:08Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
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{{2011GroupDiscussionMH}}<br />
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<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
I tried to fix the picture alignment problem in the pathogenesis section, let me know what you think. It's still not perfect, but as best as I could come up with.<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
<br />
Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
<br />
YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
<br />
<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
<br />
Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
<br />
I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
<br />
<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
<br />
Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
<br />
[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
<br />
z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
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<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
----<br />
<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
----<br />
Ryan Tran 10:55, 25 August 2011 (EST)<br />
----<br />
<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
<br />
<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
<br />
Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
<br />
Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
<br />
----<br />
<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
<br />
----<br />
<br />
Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
----<br />
Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
----<br />
<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=766792011 Group Project 82011-10-10T09:34:01Z<p>Z3389343: /* Pathogenesis */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
<br />
[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="right"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|}<br />
<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|align="right"<br />
|[[File:Heart Hypertrophy gross.jpg|220px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from '''FRDA''' patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for '''FRDA'''<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|330px|thumb|Role of FXN Gene]]<br />
|}<br />
<br />
Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the '''Frataxin''' deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential '''chelators''' are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-'''chelation''' had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated '''frataxin''' gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|330px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
Treatment of '''FRDA''' through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of '''fractin''' restoring to normal range within the nervous system and the heart, restoration of '''fractin''' levels was achieved where acetylisation of '''histones''' at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
<br />
<br />
Positive effects of '''fractin''' level restoration is signs of decrease in progression of '''FRDA'''. Therapeutic use of HDACI led to the normalization of the genetic expression of '''FRDA''' patients. Support of '''fractin''' level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to '''histones''' without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.<br />
<br />
*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of '''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA: <br />
* A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
* Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
* Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
* Antioxidants and other pharmacological treatments for Friedreich ataxia. <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
* New advances in the treatment of Friedreich ataxia: promisses and pitfalls. <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
* In children with Friedreich ataxia, muscle and ataxia parameters are associated. <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
* Neurophysiological evaluation in children with Friedreich's ataxia. <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
* Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
* Review: Evaluating the progression of Friedreich ataxia and its treatment. <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
* Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling. <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=766742011 Group Project 82011-10-10T09:18:05Z<p>Z3389343: /* Inheritance */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
<br />
[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|500px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="right"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|-<br />
|[[File:Heart Hypertrophy gross.jpg|240px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from '''FRDA''' patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for '''FRDA'''<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|330px|thumb|Role of FXN Gene]]<br />
|}<br />
<br />
Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the '''Frataxin''' deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential '''chelators''' are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-'''chelation''' had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated '''frataxin''' gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|330px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
Treatment of '''FRDA''' through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of '''fractin''' restoring to normal range within the nervous system and the heart, restoration of '''fractin''' levels was achieved where acetylisation of '''histones''' at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
<br />
<br />
Positive effects of '''fractin''' level restoration is signs of decrease in progression of '''FRDA'''. Therapeutic use of HDACI led to the normalization of the genetic expression of '''FRDA''' patients. Support of '''fractin''' level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to '''histones''' without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.<br />
<br />
*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of '''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA: <br />
* A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
* Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
* Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
* Antioxidants and other pharmacological treatments for Friedreich ataxia. <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
* New advances in the treatment of Friedreich ataxia: promisses and pitfalls. <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
* In children with Friedreich ataxia, muscle and ataxia parameters are associated. <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
* Neurophysiological evaluation in children with Friedreich's ataxia. <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
* Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
* Review: Evaluating the progression of Friedreich ataxia and its treatment. <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
* Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling. <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=766732011 Group Project 82011-10-10T09:16:26Z<p>Z3389343: /* Inheritance */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
<br />
[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|450px|thumb|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="right"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|-<br />
|[[File:Heart Hypertrophy gross.jpg|240px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from '''FRDA''' patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for '''FRDA'''<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|330px|thumb|Role of FXN Gene]]<br />
|}<br />
<br />
Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the '''Frataxin''' deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential '''chelators''' are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-'''chelation''' had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated '''frataxin''' gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|330px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
Treatment of '''FRDA''' through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of '''fractin''' restoring to normal range within the nervous system and the heart, restoration of '''fractin''' levels was achieved where acetylisation of '''histones''' at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
<br />
<br />
Positive effects of '''fractin''' level restoration is signs of decrease in progression of '''FRDA'''. Therapeutic use of HDACI led to the normalization of the genetic expression of '''FRDA''' patients. Support of '''fractin''' level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to '''histones''' without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.<br />
<br />
*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of '''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA: <br />
* A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
* Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
* Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
* Antioxidants and other pharmacological treatments for Friedreich ataxia. <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
* New advances in the treatment of Friedreich ataxia: promisses and pitfalls. <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
* In children with Friedreich ataxia, muscle and ataxia parameters are associated. <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
* Neurophysiological evaluation in children with Friedreich's ataxia. <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
* Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
* Review: Evaluating the progression of Friedreich ataxia and its treatment. <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
* Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling. <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
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'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_8&diff=766712011 Group Project 82011-10-10T09:14:19Z<p>Z3389343: /* Inheritance */</p>
<hr />
<div>{{2011ProjectsMH}}<br />
<br />
='''Friedreich’s Ataxia'''=<br />
<br />
==Introduction==<br />
[[File:Nikolaus Friedreich Portrait.jpg|230px|thumb|Nikolaus Friedreich Portrait]]<br />
Friedreich’s Ataxia [[#Glossary | '''(FRDA)''']] is an extremely debilitating progressive neurodegenerative disease. FRDA, an autosomal recessive disorder, is the most common of the inherited ataxias and affects an estimated 1 in 50,000 people. <ref name="PMID11351269"><pubmed>11351269 </pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Patients suffering from FRDA have a normal presentation at birth and for a period of time thereafter. When the patient reaches the age of onset, which is approximately around the time of puberty, the clinical [[#Glossary | '''phenotypes''']] become noticable, such as [[#Glossary | '''ataxic gait''']]. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> Progressive weakness is also noticeable due to loss of skeletal muscle, which can cause pateints to become wheelchair bound with in 10-15 years of onset of the disease. <ref name="PMID19283344" /> <br />
<br />
FRDA is caused by a mutation in the [[#Glossary | '''frataxin''']] gene. The disruption of the frataxin gene is often caused by a [[#Glossary | '''trinucleotide''']] repeat expansion of [[#Glossary | '''GAA''']], which is located on chromosome 9q13. <ref name="PMID11351269" /> The product of this gene is a mitochondrial protein, frataxin, which is known to play a role in iron [[#Glossary | '''homeostasis''']]. <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> This causes major disabilities in the tissues containing the frataxin deficient mitochondria, such as skeletal and cardiac muscle, as well as, the central and peripheral nervous systems. <ref name="PMID12547248"><pubmed>12547248</pubmed></ref> <br />
<br />
The results of FRDA involve an increase chance of developing diabetes mellitus and premature death due to congestive cardiac failure and [[#Glossary | '''cardiac arrhythmia''']]. <ref name="PMID10633128" /> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID5673214"><pubmed>5673214</pubmed></ref><br />
<br />
==History==<br />
<br />
<br />
Nikolaus (Nicholas) Friedreich (1825-1882) was born into a family of physicians and studied medicine at the University of Würzburg, Germany. Pathology and neurology were his main interests in medicine and in 1858 he became the director of medicine at the Heidelberg medical clinic. <ref name="PMID19283344" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> During his years at Heidelberg he became intrigued with the clinical presentation of some of his patients who he described as having “degenerative atrophy of the posterior columns of the spinal cord that could affect several children of unaffected parents”. <ref name="PMID19283344" /> <br />
<br />
In 1863, Friedreich wrote his first journal article on his findings about six of his patients who belonged to two separate families. These patients presented with similar clinical signs and with his continued research Friedreich collated the symptoms of ataxic gait, sensory loss, dysarthria, skeletal muscle weakness, foot irregularities, [[Glossary|'''scoliosis''']] and cardiac abnormalities linking there cause to a common factor. <ref name="PMID10633128" /> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref> Friedreich proceeded to write several articles on the disease, which now bares his name Friedreich’s Ataxia. <br />
<br />
===Timeline===<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Date'''<br />
| '''Significance'''<br />
|- bgcolor="Azure"<br />
| '''1863''' <br />
| Friedreich describes the clinical presentation of patients and publishes his findings. <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1882''' <br />
| Brousse ''et al'' suggests that many diseases have been mistaken for FRDA, such as Charcot-Marie-Tooth disease or syphilis, which called for further investigation and classification techniques for FRDA <ref name="PMID10633128"><pubmed>10633128</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1907''' <br />
| A study by Mott ''et al'' gave the first detailed description of the dentate nucleus and the role it plays in FRDA pathology. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1976''' <br />
| The Québec Collaborative Group proposed a systematic way of classifying and diagnosing FRDA, such as the absence of tendon reflexes. <ref name="PMID20156111"><pubmed>20156111 </pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1980'''<br />
| FRDA patients were found to have iron-positive granules deposited within [[#Glossary | '''cardiomyocytes''']], as well as, skeletal muscle fibres. <ref name="PMID:6452194"><pubmed>6452194</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1988''' <br />
| The chromosomal locus for FRDA was mapped to chromosome 9q13. <ref name="PMID10607838"><pubmed>10607838</pubmed></ref> <ref name="PMID15090560"><pubmed>15090560</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1989'''<br />
| Wallis ''et al'' developed the first prenatal diagnostic test for FRDA via [[#Glossary | '''DNA''']] markers. <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1990''' <br />
| Two closer DNA markers were establish by Hanauer ''et al'' improving prenatal test to almost 99%. <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> <br />
|- bgcolor="Azure"<br />
| '''1995''' <br />
| Monros ''et al'' refined prenatal testing in regards to new [[#Glossary | '''recombination''']] techniques available with an accuracy close to 100%. <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1996''' <br />
| Frataxin, the mutated gene responsible for FRDA, was discovered by Campuzano ''et al'', which allowed for molecular testing and full clinical classification of the disease. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <ref name="PMID10607838"><pubmed>10607838</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''1997''' <br />
| Rötig ''et al'' reported on the defective activity of the iron-sulphur clusters in FRDA patients, in relation to mitochondrial respiratory complexes I, II and III via a yeast homologue. They also discovered the protein [[#Glossary | '''aconitase''']] to also be deficient with in patients, thus suggesting that iron accumulation is a key component in FRDA pathogenesis. <ref name="PMID: 9326946"><pubmed>9326946</pubmed></ref> <br />
|-bgcolor="Azure"<br />
|<br />
|Whilst researching the GAA trinucleotide repeat expansion Cossée ''et al'' uncovered that nearly 17% of expansions consisted of repeats longer than 16 GAA. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''2002''' <br />
| Mühlenhoff ''et al'' demonstrated, via a yeast frataxin homologue (YFH1), that the decreased maturation of iron-sulphur proteins and accumulation of mitochondrial iron are critical factors in oxidative stress in FRDA. <ref name="PMID:12165564"><pubmed>12165564</pubmed></ref><br />
|- bgcolor="Azure"<br />
| '''Current'''<br />
| Research is looking into treatments for FRDA and Idebnone, which may reverse the [[#Glossary | '''redox''']] reaction associated with FRDA looks very promising. <ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><br />
|<br />
|}<br />
<br />
==Epidemiology==<br />
'''Distribution'''<br />
{|align="right"<br />
|[[File:GAA Frequency in FRDA.jpg|470px|thumb|Graph of the Frequency of GAA Repeat in FRDA Patients across Four Different Populations]]<br />
|}<br />
FRDA is the most common form of inherited ataxic disease, affecting an estimated 1 in 50,000 people. <ref name="PMID10633128" /> <ref name="PMID11351269"><pubmed>11351269</pubmed></ref> <ref name="PMID19283344" /><br />
<br />
'''Populations''' <br />
<br />
It has been noted that FRDA has a range of prevalence’s in accordance to the country of interest. Caucasian populations have a higher prevalence of FRDA with approximate carrier frequencies varying between 1:50 to 1:100. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref> This includes Australia, the United States of America and similar European countries, which have the aforementioned prevalence of 1 in 50,000. <ref name="PMID20374234"><pubmed>20374234</pubmed></ref> FRDA also has a high prevalence in North Africa, the Middle East and India. <br />
<br />
Studies performed in Italy revealed an extremely high birth incidence of FRDA with the disease affecting 4.9 in every 50,000 live births. <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
Some Southern and Central American countries, such as Cuba, have a much lower prevalence of FRDA approximately 1 in 2,200,00 in addition to lower carrier frequencies of 1:745. <ref name="PMID20569261"><pubmed>20569261</pubmed></ref> Furthermore, Asian, sub-Saharan African and Amerindian populations have a much lower prevalence or the FDRA genetic mutation is non existent. <ref name="PMID21315377" /> <ref name="PMID10633128"><pubmed>10633128</pubmed></ref> <ref name="PMID14767759"><pubmed>14767759</pubmed></ref><br />
<br />
'''Gender''' <br />
<br />
There has been no gender differentiation at this point in time, therefore, males and females have the same chance of inheriting FRDA. <ref name="PMID21315377" /><br />
<br />
'''Age''' <br />
{|align="right"<br />
|[[File:Symptoms and signs in FRDA patients.jpg|470px|thumb|The Percentage of the Symptoms and Signs in a group of FRDA Patients]]<br />
|}<br />
<br />
Onset of FRDA is relatively early in life with symptoms normally appearing between 5-15 years of age, typically, patients are diagnosed before the age of 20. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> There are cases of late onset FRDA in which symptoms begin to show around 28 ± 13 years of age, remarkably these patients are less affect by cardiac dysfunction but are most likely to fall ill to neurological disability. <ref name="PMID21128039"><pubmed>21128039</pubmed></ref> Furthermore, there have been known cases of very late onset FRDA but these cases are fairly uncommon and occur beyond the age of 40. <ref name="PMID16092110"><pubmed>16092110</pubmed></ref><br />
<br />
''' Morbidity & Mortality''' <br />
<br />
FRDA is a progressive disease causing 95% patients to become wheelchair-bound by approximately 45 years of age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Commonly, patients tend to lose the capability to walk nearing the age of 25. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> Death of FRDA patients is principally triggered by cardiac dysfunction. In a study performed by Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> 59% of patients died due to cardiac dysfunction, such as congestive cardiac failure and arrhythmia. 27.9% of patients died due to non-cardiac dysfunction, including [[#Glossary | '''pneumonia''']], [[#Glossary | '''sepsis''']] and renal failure and the remaining patients died of unknown causes. <ref name="PMID21652007"><pubmed>21652007</pubmed></ref> <br />
Death of FRDA patients remains quite young with the age of passing around 37.7 years of age ±14.4 years with patients suffering from cardiac dysfunction dying at an earlier age. <ref name="PMID7272714"><pubmed>7272714</pubmed></ref> <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
<br />
==Aetiology==<br />
===Genetic Component===<br />
<br />
[[File:The frataxin gene on chromosome 9.jpg|thumb|The frataxin gene on chromosome 9]]<br />
The frataxin gene is located on the proximal long arm of chromosome 9. Its location was identified for the first time by Chamberlain ''et al'' (1988) <ref name="PMID2899844"><pubmed>2899844</pubmed></ref>, using a [[#Glossary | '''linkage study''']] for the mapping. Subsequent studies further refined the location to 9q13-q21 <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>.<br />
<br />
The most common mutation leading to the FRDA phenotype is an expansion of the GAA [[#Glossary | '''triplet repeat''']] in the first [[#Glossary | '''intron''']] of the frataxin gene. Repeats up to approximatively 40 are normal, and manifestations of the disease start at 70 repeats. The repeat number can reach up to 1700, and the most common number of repeats in FRDA patients is between 600-900<ref name="PMID21827895"><pubmed>21827895</pubmed></ref> <ref name="PMID9207112"><pubmed>9207112</pubmed></ref>. The mutation is recessive, thus [[#Glossary | '''heterozygous''']] carriers of the repeat are clinically normal. Most FRDA patients are [[#Glossary | '''homozygous''']] for a repeat expansion, although there are some rare cases of heterozygous patients who have a repeat expansion on one allele and a [[#Glossary | '''missense''']] or [[#Glossary | '''nonsense point mutation''']] on the other allele. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
'''Evolution'''<br />
<br />
FRDA is the most common repeat-expansion caused disease, with as many as 1 in 90 [[#Glossary | '''carriers''']] in the European population. While repeats up to 40 do not show any clinical manifestations, most normal repeats are smaller, consisting of only 8-9 repeats. In a study investigating the evolution of the repeat expansion, Cossée ''et al'' (1997) <ref name="PMID9207112"><pubmed>9207112</pubmed></ref> found that only approximately 17% of clinically normal repeats consist of repeats longer than 16.<br />
The comparatively high prelevance of FRDA in European populations compared to other populations has been suggested to be the result of a [[#Glossary | '''founder event''']]. The presence of long repeat alleles without clinical manifestations served as a pool for further length variations, including transitions to pathological repeat expansions. In some cases, this transition has been achieved within one single generation. <ref name="PMID9207112"><pubmed>9207112</pubmed></ref><br />
<br />
'''Genetic Instability'''<br />
<br />
Several other disorders, including Fragile X Syndrome, Huntington's Disease as well as other ataxias, are caused by repeat expansions, suggesting the possibility of a common underlying mechanism. Indeed, repeat regions, especially trinucleotide repeats, are generally unstable structures and can undergo additions or deletions of the repeated unit <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>. The cause for this instability is replication slippage: during DNA [[#Glossary | '''replication''']], one strand of the DNA template may loop out and become displaced, alternatively, [[#Glossary | '''DNA polymerase''']] might slip or stutter. Both of these scenarios lead to either replication of already replicated sequences when the DNA polymerase rebinds to the template, which thus leads to expansions, or alternatively, DNA polymerase might rebind further down the strand, thus failing to replicate part of the sequence, leading to deletions. Replication slippage is a lot more common in repeat regions, and furthermore, the longer the repeat, the more likely slippage is to occur. (For further detail on the mechanisms of replication slippage, see Viguera ''et al'' (2001) <ref name="PMID11350948"><pubmed>11350948</pubmed></ref>.)<br />
This observation explains why a pathological repeat expansion can be achieved within very few generations if the parental alleles are longer variants of the normal repeat length. This further explains the anticipating pattern of inheritance in families with the disease, further discussed in the Inheritance section.<br />
<br />
===Inheritance===<br />
<br />
Friedreich's Ataxia is a recessive disease, meaning that an individual needs to carry two copies of the mutated frataxin allele to manifest the disease.<br />
As already mentioned, a normal long repeat can lead to a pathologically long expansion within only one generation. Thus a person can inherit a disease allele from a parent carrying two normal alleles. Alternatively, an individual may inherit a pathological allele from both parents who could be heterozygous, healthy carriers.<br />
Due to the length of the repeat making it more unstable and likely to expand further as well as the correlation between repeat length and the severity of symptoms, FRDA presents an anticipating pattern of inheritance. Over the course of a few generations in an affected family, the age of onset of the disease decreases while the severity of symptoms increases. <ref name="PMID21827895"><pubmed>21827895</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Friedreich's Ataxia Pedigree.png|450px|Friedreich's Ataxia Pedigree]]<br />
|}<br />
<br />
===Genetic Expression===<br />
{|align="right"<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|265px|thumb|Gene expression responses of Friedreich's ataxia]]<br />
|}<br />
The frataxin gene is expressed in all cells, though the expression levels vary between different tissues and at different times during development. <br />
<br />
In adult cells, frataxin levels are highest in the heart, brain and spinal cord, followed by the liver, skeletal muscle and the pancreas. Generally, the frataxin levels are higher in cells that are abundant in mitochondria, such as cardiomyocytes and neurons <ref name="PMID21827895"><pubmed>21827895</pubmed></ref>. Nevertheless, some cell specificity, such as primary sensory neurons, still remains unexplained.<br />
<br />
Developmental expression has been investigated in mouse embryos <ref name="PMID9331900"><pubmed>9331900</pubmed></ref>, and it was found that frataxin is expressed during embryonic development, though generally at a lower level than postnatally. The highest prenatal level of expression was found in the spinal cord, followed by the [[#Glossary | '''periventricular''']] zone, the [[#Glossary | '''cortical''']] plates and the heart. This distribution is in concordance with the distribution observed in adults, the only exception being expression in the cerebral cortex, which has not been manifested in adults. Overall, it seems that the tissues expressing frataxin during embryonic development are the ones that become dysfunctional in adults suffering from FRDA.<br />
Further studies on mouse models have shown that if the frataxin gene is completely knocked out, the embryo does not survive, indicating that the frataxin gene is needed for early development<ref name="PMID:10767347"><pubmed>10767347</pubmed></ref>.<br />
<br />
===Silencing of the frataxin gene (consequences of the mutation)===<br />
<br />
In a study investigating the consequences of the repeat expansion for DNA transcription, Bidichandani ''et al'' (1998) <ref name="PMID9443873"><pubmed>9443873</pubmed></ref> found that [[#Glossary | '''splicing''']] of the expanded intron is not affected, and thus is not the cause for abnormal frataxin protein. Instead, they showed that [[#Glossary | '''mRNA''']] levels of frataxin are very low in FRDA patients, speaking for ineffective transcription. Indeed, they showed in further experiments that the GAA triplet expansion interferes with transcription. This interference is length dependent, and here a threshold of 79 GAA repeats was found before interference occurs. Furthermore, the interference is orientation specific, it only occurs during the synthesis of the GAA transcript which is the physiological direction of transcription, and not in the complementary strand transcript. The reason for this interference is assumed to be the formation of unusual DNA structures. Both G (guanine) and A (adenine) are [[#Glossary | '''purines''']] while T (thymine) and C (cytosine) are [[#Glossary | '''pyrimidines''']]. Thus a GAA repeat leads to a strand of pure purines binding to a complementary strand of pure pyrimidines. Such structures have been found to form unusual DNA structures, and it is assumed that this is also the case in the GAA repeat in the frataxin gene. These unusual structures are also present in the shorter GAA repeats which don't lead to transcription interference, and it is thought that a longer repeat stabilises the unusual structure. <br />
<br />
It is thought that these unusual structures interfere with the transcription, thus making longer repeats more stable and more efficient in the transcription blockage, which leads to [[#Glossary | '''gene silencing''']]. This would account for the negative correlation between repeat length and frataxin mRNA levels as well as frataxin levels as such. <ref name="PMID9443873"><pubmed>9443873</pubmed></ref><br />
More recent studies are looking at whether the elongation and/or the initiation of transcription are affected. While it is generally accepted that there are problems with the elongation in repeat expansions, some have found evidence for inhibited initiation, though this is still a matter of debate. <ref name="PMID21127046"><pubmed>21127046</pubmed></ref> <ref name="PMID20373285"><pubmed>20373285</pubmed></ref><br />
<br />
In the rare cases of heterozygous individuals with a repeat expansion and a point mutation, the point mutation most often leads to either a shortened or abnormal frataxin protein, which is unfunctional. <ref name="PMID 20156111"><pubmed> 20156111 </pubmed></ref><br />
<br />
The protein frataxin is a mitochondrial protein which is thought to be involved in mitochondrial iron metabolism. It is the deficiency in frataxin which leads to the clinical manifestations of FRDA.<br />
<br />
==Pathogenesis==<br />
<br />
{|align="right"<br />
|[[File:Pathogenesis of Friedreich Ataxia.jpg|300px|thumb|A model of pathogenesis in Friedreich's Ataxia]]<br />
|-<br />
|[[File:Heart Hypertrophy gross.jpg|240px|thumb|Gross and microscopic view of heart with and without hypertrophy]]<br />
|}<br />
<br />
As FRDA is a ‘neurodegenerative disorder’ patients with FRDA are normal at birth until the ‘age of onset’ where symptoms present<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref> due to (what is believed to be) iron build up in mitochondria. In humans, the GAA repeat expansion on the frataxin gene causes a transcription defect on the gene impairing it's ability to produce frataxin (a mitochondrial protein). As a result, incorrect recruitment and utilisation of iron in mitochondria allows an increase of available iron in mitochondria to produce too much oxidants which would damage cells<ref name="PMID10633128"><pubmed>10633128</pubmed></ref>. <br />
<br />
Cardiomyopathy is caused by build up of iron in mitochondria producing excessive amounts of free radicals and anti-oxidants which damages cells. As Frataxin is most expressed in the heart, skeletal muscles, (as well as liver and pancreas)and nervous system <ref name="PMID:10633128"><pubmed>10633128 </pubmed></ref>, it impacts most significantly on the nervous system followed by musculature and cardiac muscles. For more information on nervous systems impacts see Neuropathology.<br />
<br />
===Cardiomyopathy===<br />
In the past, the pathogenesis of cardiomyopathy in FRDA patients was relatively unknown<ref name="PMID3593615"><pubmed>3593615</pubmed></ref>, however it is now believed that the buildup of iron in mitochondria within cardiac muscle is part of the pathogenesis in cardiomyopathy of FRDA patients<ref name="PMID18621680"><pubmed>18621680</pubmed></ref>. The iron build up results in what is described as ‘Fenton Chemistry’ where the excessive amounts of iron that are recruited into the mitochondria will produce a large quantity of HO˙. The production of HO˙ is of concern as it is a hydroxyl radical which is toxic to cells and it reacts to a variety of intracellular components including DNA<ref name="PMID10633128"><pubmed>10633128</pubmed></ref> resulting in cardiac damage and resulting cardiomyopathy.<br />
<br />
The length of the GAA repeat on the frataxin gene also has an impact on the pathogenesis of cardiomyopathy as it was discovered that the degree of ventricular hypertrophy is related to the length of the GAA repeat <ref name="PMID:11269509"><pubmed>11269509</pubmed></ref>. Patients with no signs of cardiomyopathy and late onset of symptoms have also been reported having shorter GAA repeats <ref name="PMID:9339708"><pubmed>9339708</pubmed></ref> <ref name="PMID:18759347"><pubmed>18759347</pubmed></ref>.<br />
<br />
Associated muscular problems in FRDA such as hypotonia and hyperreflexia can be attributed to axonal degeneration in the spinocerebellar tract. For more information on muscular pathogenesis, see neuropathy.<br />
<br />
===Neuropathology===<br />
FRDA produces a complex neuropathological phenotype within the central nervous system [[#Glossary | '''(CNS)''']], as well as, the peripheral nervous system [[#Glossary | '''(PNS)''']] and it is the neuropathology that differentiates this disease from other forms of hereditary ataxia. FRDA patients present with distinctive lesions of dorsal root ganglia [[#Glossary | '''DRG''']], dorsal spinal roots, [[#Glossary | '''dorsal nuclei of Clarke''']], spinocerebellar and corticospinal tracts, cerebellum, dentate nuclei, and sensory nerves. <ref name="PMID19957189"><pubmed>19957189</pubmed></ref><br />
<br />
FRDA patients have consistent lesions in the DRG, which trigger secondary degeneration of the fibers in the spinocerebellar tracts and atrophy of the neurons in the dorsal nuclei Clarke. Less consistent among FRDA patients are lesions occurring in the dentate nucleus, in addition to optic [[#Glossary | '''atrophy''']], and degeneration of the corticospinal tract.<br />
<br />
<br />
'''The Dorsal Root Ganglia''' <br />
<br />
The hallmark of FRDA involves atrophy of the DRG and thinning of dorsal roots themselves within the PNS, refer to the figure of the Cross Section of the Spinal Cord. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> The lesions of the large primary neurons in the DRG are an early clinical finding in the disease with neuropathological examinations of FRDA patients showing a decreased size of DRG along with grey staining of the thinned dorsal roots . <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> <br />
Iron dysfunction, caused by mutation of the frataxin gene, highly affects the DRG causing a common characteristic of the disease, which includes [[#Glossary | '''demyelination''']] and unsuitable regeneration of myelin of the dorsal root. <ref name="PMID19727777"><pubmed>19727777</pubmed></ref> <ref name="PMID19679182"><pubmed>19679182</pubmed></ref><br />
<br />
The study by Mott ''et al'', (1907) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> highlighted the importance of the DRG, in which Friedreich himself did not seem to think played any role in this disease. It has been suggested that DRG pathology involves an age determined buildup of the GAA triplet repeat sequence “…thus, somatic instability of the expanded GAA [[#Glossary | '''triplet-repeat''']] sequence may contribute directly to disease pathogenesis and progression.” <ref name="PMID17262846"><pubmed>17262846</pubmed></ref> Furthermore, the experiment conducted by Lu ''et al,'' (2009) <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> measured the significance of frataxin depletion in [[#Glossary | '''Schwann cell''']] and [[#Glossary | '''oligodendrocyte cell''']] lines. Results showed that mainly Schwann cell succumbed to cell death and reduced proliferation. This highlights that the Schwann cells, which enwrap DRG are affected greatly by frataxin deficiency. <ref name="PMID19679182"><pubmed>19679182</pubmed></ref> <br />
<br />
When abnormalities arise in Schwann cell, due to injury or genetics, they can cause demyelination, inappropriate proliferating and [[#Glossary | '''phagocytosis''']] of debris. <ref name="PMID21878126"><pubmed>21878126</pubmed></ref> The understanding of the pathological change within the peripheral nervous system is poorly understood, however, the damaged DRG seems be the basis of FRDA. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Damage and/or loss of the [[#Glossary | '''neurons''']] of DRG are seen to be the primary manifestations of FRDA many secondary affects stem from this area, such as;<br />
* The depletion of the centrally projecting [[#Glossary | '''axons''']] of the DRG into the dorsal root. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* The loss of axons in the dorsal root explains the depletion of the dorsal column fibers and “…afferent connections to the dorsal nuclei of Clarke and the [[#Glossary | '''grey matter''']] of the dorsal horns.” <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
<br />
{|align="center"<br />
|[[File:Cross Section of the Spinal Cord.jpg|600px|thumb|Cross Section of the Spinal Cord]]<br />
|}<br />
<br />
'''The Dorsal Nuclei of Clarke'''<br />
<br />
The dorsal nuclei of Clarke are mainly found in the thoracic region of the spinal cord. These nuclei function to relay [[#Glossary | '''proprioceptive''']] information from the lower extremities to the spinocerebellar tract. The information this nucleus receives arises from muscle spindles and Golgi tendon organs. Within the spinal cord the nuclei can be located in the intermediate grey matter, refer to the figure of the Cross Section of the Spinal Cord. It is within the grey matter that the dorsal nuclei of Clarke form synapses with the dorsal spinocerebellar tract, which will continue transmitting the sensory information in a rostral direction until it reaches the spinocerebellum. <br />
<br />
When FRDA abnormalities occur in this area it will assist in proprioceptive sensory loss, of mainly the lower extremities. This would contribute to clumsiness and unexplained falls before FRDA patients are wheel chair bound. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
<br />
<br />
'''The Spinocerebellar Tract'''<br />
{|align="right"<br />
|[[File:The Babinski Reflex.jpg|240px|thumb|The Babinski Reflex]]<br />
|}<br />
<br />
This spinal pathways is involved in passing sensory information from the spinal cord to the brain and/or cerebellum. The function of this tract is to carry proprioceptive information to the cerebellum, which allows the integration of sensory information with movement. The spinocerebellum is the only area of the cerebellum that receives peripheral sensory input. Specifically, this tract aids in ongoing control of voluntary movement, motor control, locomotion, posture and ongoing execution via its connection to the spinocerebellum.<br />
<br />
Notably, the lesions tend to occur in the dorsal spinocerebellar tract and are said to be secondary to DRG lesions. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref> Post mortem examination of patients suffering from FRDA are indicative of a small, atrophied spinal cord with degeneration in the dorsal columns, spinocerebellar and corticospinal tracts. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref><br />
<br />
<br />
Pathogenesis of the spinocerebellar tract includes axonal degeneration, which is characterized by demyelination of the myelin sheath encapsulating the axon, which normally allows for rapid propagation of electrical impulses. Followed by degeneration of the underlying axon, which will in turn disrupt the function of the spinocerebellum itself causing symptoms, such as: <br />
* “…loss of spinocerebellar input to the cerebellar hemispheres due to transneuronal atrophy of the dorsal nuclei of Clarke.” <ref name="PMID21638087"><pubmed>21638087</pubmed></ref><br />
* [[#Glossary | '''Hypotonia''']] is the loss of muscle tone, which is variable between the upper and lower extremities, with muscle tone being usually normal in the arms but the tone of the legs, can differ. <ref name="PMID21315377"><pubmed>21315377</pubmed></ref><br />
* Loss of position and vibration sense, which leads into [[#Glossary | '''dysmetria''']] . (Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk] ) <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* [[#Glossary | '''Ataxia gait''']] (Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related] )<br />
* Intention tremor nearing target.<br />
* [[#Glossary | '''Hyperreflexia''']] in the lower extremities is common among patients, in which there is unrestricted flow of excitation to the motoneurons causing spastic movements. (Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg] )<br />
* Decreased or abolished tendon reflexes along with sensory deprivation in corresponding dermatome. <ref name="PMID19283344"><pubmed>19283344</pubmed></ref><br />
* Diminished ability to perceive touch, light, temperature and pain, which is more prominent in the lower extremities.<br />
* [[#Glossary | '''Positive Babinski reflex''']] (extensor plantar responses) and muscle weakness. (Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related] )<br />
<br />
<br />
'''The Cerebellum'''<br />
{|align="right"<br />
|[[File:Lateral View of the Brain.jpeg|300px|thumb|Lateral View of the Brain]]<br />
|}<br />
<br />
The cerebellum (Latin for “little brain”) is a small structure that creates the hindbrain and is enclosed by the occipital bone, refer to the figure of the Lateral View of the Brain. The cerebellum contains more than 50% of the brains neurons but only takes up 10% of the human brains total volume. This densely packed structure is involved in:<br />
* Adjusting the outputs of the descending motor pathways, as it receives massive input from the motor cortex in the brain, as well as sensory receptors.<br />
* Regulatory functions in movement and posture, which allows the cerebellum to compare and evaluate motor/sensory discrepancies, which provide corrective responses.<br />
* Producing projections into the descending motor pathways. <br />
<br />
<br />
The three functional nuclei of the cerebellum, namely the dentate, interposed and fastigial all play a central role in relaying information between the cortex and other brain structures, refer to the figure of the Transverse Section of the Cerebellum. <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> In FRDA the degeneration of cerebellum appears late in the course of the disease becoming apparent upon neurological examination when Purkinje fibre depletion can be seen and atrophy of the dentate nuclei is observable. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref><br />
<br />
<br />
'''The Dentate Nucleus''' <br />
<br />
Out of the three nuclei of the cerebellum the dentate nucleus undergoes considerable atrophy and has been said to be the most likely cause of the symptoms dysmetria, [[#Glossary | '''dysarthria''']] , [[#Glossary | '''dysphagia''']]. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> The dentate nucleus has axonal “…projections into the motor, premotor, oculomotor, prefrontal and posterior parietal cortex,” <ref name="PMID21107777"><pubmed>21107777</pubmed></ref> thus with degeneration at the dentate nucleus can cause secondary abnormalities at the aforementioned areas. <br />
Frataxin deficiency causes iron accumulation with in the mitochondria, which in turn cases oxidative damage. This may be responsible for the neuronal loss but further research is needed in this area before any definitive answers can be given. <br />
<br />
<br />
The cerebellum connects to the brainstem via the superior, middle and inferior peduncles. Upon post mortem dissection many FRDA patient’s display degeneration of the superior peduncles; this is where the efferent fibres of the dentate nucleus can be located. Interestingly, only large neuronal cells of this nucleus undergo atrophy, which highlights the selective nature of FRDA and the small neurons remain unaffected, however, further research needs to be complete before the reason for the selectivity is understood. <ref name="PMID21638087"><pubmed>21638087</pubmed></ref> <br />
{|align="right"<br />
|[[File:Transverse section of the Cerebellum.jpg|300px|thumb|Transverse Section of the Cerebellum- Highlighting the three nuclei]]<br />
|}<br />
<br />
<br />
'''The Corticospinal Tract'''<br />
<br />
This descending pathway conveys information from the motor areas of the brain to the spinal cord. This spinal tracts is of great importance as it can direct or indirectly control the movement of muscles. The corticospinal tract is made up of two pathways:<br />
# Lateral- which projects axon onto motoneurons and/or interneurons of distal muscles. <br />
# Ventral- which projects axon onto motoneurons and/or interneurons of axial muscles. <br />
<br />
<br />
It has been noted that in particular the distal portions of the corticospinal pathway fibers are severely affected, suggesting a dying-back degeneration. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> Dying-back degeneration implies that degeneration occurs at the most proximal end of the axon and destructively works its way up toward the neuron. Within the cerebral cortex the corticospinal tract originates from pyramidal or Betz cells in which degeneration is apparent but to a reduced extent. <ref name="PMID12878293"><pubmed>12878293</pubmed></ref> <br />
<br />
Results of lesion of the corticospinal tract can produce:<br />
* Muscle weakness, mainly of the lower extremities and is most prominent in extensors and abductors of the hip. <ref>Bidichandani SI, Delatycki MB. In: Pagon RA, Bird TD, Dolan CR, Stephens K (editors) '''Friedreich Ataxia.''' GeneReviews: 1998 </ref><br />
* Positive Babinski reflex indicate involvement of the corticospinal tracts.<br />
<br />
==Clinical Presentation== <br />
{|align="right"<br />
|-<br />
| [[File:Scoliosis drawn.jpg|thumb|100px|Schematic drawing of scoliosis]]<br />
|-<br />
| [[File:Pes Cavus Deformity.jpg|240px|thumb|Pes Cavus Foot Deformity]]<br />
|}<br />
===Symptoms===<br />
<br />
Friedreich's Ataxia (FRDA) often manifests before puberty to early adulthood. Previous papers setting guidelines for the diagnosis of FRDA and was first established by Geffory ''et al''. (1976)<ref name="PMID:1087179"><pubmed>1087179</pubmed></ref> includes the symptoms of ataxia of limb and gait, onset before 20 years of age, absent reflexes in lower limbs, dysarthria, loss of peripheral sense ([[#Glossary | '''proprioception''']]), muscle weakness and sensory loss on the back<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. It was then revised by Harding (1981)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref> to exclude muscle weakness and sensory loss on the back, dysarthria and to include the onset of FRDA before the age of 25, ataxia of gait, and absent reflexes in the leg<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
As evident between Harding and Geffory, there are variations between authors on symptoms considered to be primary.<br />
Physical complaints such as chest pains <ref name="PMID:7488466"><pubmed>7488466</pubmed></ref> <ref name="PMID:3593615"><pubmed>3593615</pubmed></ref> indicative of cardiomyopathy scoliosis, foot deformity [[#Glossary|'''pes cavus''']], hammer toe), extensor plantar responses (Babinski's sign), and dysarthria* (Dysarthria was considered a secondary symptom by Harding but a primary symptom by Geffory) are common and are often classified as secondary symptoms before FRDA is suspected<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
For more information on past diagnostic guidelines and current suggested diagnostic practice, see diagnosis.<br />
Other symptoms associated with FRDA such as a direct consequence of neurodegeneration such as hyperreflexia and hypotonia amongst the others already mentioned had not been mentioned by Harding or Geffory but are important to note as they are a direct consequence of FRDA. For more information see the section on neuropathology.<br />
<br />
The table below summarises symptoms of FRDA as primary or secondary.<br />
<br />
{| style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Classification of symptom'''<br />
| '''Type of symptom'''<br />
|-bgcolor="Azure"<br />
| '''Primary'''<br />
| Ataxia of limb and gait<br />
Absent reflexes in lower limbs<br />
<br />
Onset before 25 years of age<br />
<br />
Loss of peripheral sense (proprioception)<br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Secondary'''<br />
| Scoliosis <br />
Pes Cavus<br />
<br />
Extensor plantar responses (Babinski's sign)<br />
<br />
Dysarthria<br />
|}<br />
<br />
===Complications===<br />
<br />
Complications of FRDA can have cardiac and pancreatic involvement as a secondary result of mitochondrial iron accumulation. Cardiac involvement is high (>90%)<ref name="PMID:12045843"><pubmed>12045843</pubmed></ref>, and it is hypothesised that FRDA exacerbates existing cardiac risk factors and increases the chance of developing cardiomyopathy (eg: ventricular [[#Glossary|'''hypertrophy''']] and [[#Glossary|'''tachycardia''']])<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>.<br />
Even in Friedreich's original description of his patients, 5 out of 6 patients had cardiac involvement<ref name="PMID:17622372"><pubmed>17622372</pubmed></ref>. Familial links in cardiomyopathy and familial groups affected with FRDA has been found to exist(P <0.01). Though it does not show as great a relationship of development to familial FRDA groups as diabetes <ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>. For more information on cardiomyopathy in FRDA, see pathogenesis.<br />
<br />
Diabetes as a complication of FRDA is fairly straight forward with a clear reason as to why it occurs. In mouse models of FRDA, when the frataxin gene is disrupted the overall volume of beta-cells is reduced due to cell [[#Glossary|'''apoptosis''']], loss of beta-cell proliferation and increased [[#Glossary|'''Reactive Oxygen Speices (ROS)''']] in islets which would damage pancreatic cells if not in check<ref name="PMID:12925693"><pubmed>12925693</pubmed></ref>.<br />
It was found that the incidence of diabetes increases with sibling-ship relationships (P< 0.001)<ref name="PMID:7272714"><pubmed>7272714</pubmed></ref>.<br />
<br />
==Diagnosis==<br />
<br />
As diagnostic criterias were set before genetic screening was available, the diagnostic criteria was split into two categories of 'primary' and 'secondary' symptoms of which, primary symptoms were required for a diagnosis of FRDA and secondary symptoms acted as supporting evidence but diagnosis could not be made due to the possibility of other diseases which presented with those symptoms<ref name="PMID:10633128"><pubmed>10633128</pubmed></ref>.<br />
<br />
In a more recent review of FRDA diagnostic criteria, it is proposed that new three categories (not using the dated categories) of 'possible', 'probable' and 'definite' indicating the ''likelihood'' of FRDA should be used instead. Additionally, it was suggested to include lower limb areflexia and dysarthria, babinski's sign, or repolarisation abnormalities on the electrocardiogram (ie: abnormal T-wave) or repolarisation abnormalities in patients with retained lower limb reflexes to be able to make a possible diagnosis of FRDA<ref name="PMID:11104216"><pubmed>11104216</pubmed></ref>. <br />
<br />
Currently, patients who are suspected of having FRDA based on signs and symptoms (all adapted from previous FRDA diagnosis guidelines) are sent for genetic testing and are only diagnosed with FRDA after genetic testing confirms the diagnosis of FRDA.<br />
<br />
===Diagnostic Tools===<br />
<br />
The table below shows common diagnostic tools employed in the diagnosis of FRDA:<br />
<br />
{|style= border="0"<br />
|- bgcolor="LightSeaGreen"<br />
| '''Diagnostic tool'''<br />
| '''What it does'''<br />
| '''How it diagnoses FRDA'''<br />
| '''Image (if available)'''<br />
|- bgcolor="Azure"<br />
| '''Electromyogram''' (EMG)<br />
| Measures the electrical activity of muscle cells by inserting needles into muscle fibers that is to be tested and asking the patient to tense the muscle<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| EMG can detect denervation<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref> such as present in motor neuron diseases or muscle denervation as present in FRDA.<br />
| Electromyograph test (video): [http://youtu.be/UzbcH16AUzE]<br />
|- bgcolor="Azure"<br />
| style="white-space: nowrap" | '''Electrocardiogram''' (ECG)<br />
| Provides graphic presentation of the electrical activity or beat pattern of the heart<br />
| If [[#Glossary|'''T wave inversion''']] is present, it may be an indication myocardial hypertrophy<ref name="PMID:19486532"><pubmed>19486532</pubmed></ref> which is a hallmark of cardiac involvment in FRDA. T wave inversions are also common findings in patients with FRDA<ref name="PMID:3593615"><pubmed>3593615</pubmed></ref>.<br />
| [[File:Schematic ECG normal and inverted T-wave.jpg|thumb|Schematic ECG comparing normal and inverted T-waves]] Normal ECG(video):[http://youtu.be/Q0JMfIVaDUE]<br />
|- bgcolor="Azure"<br />
| '''Echocardiogram''' (ECHO)<br />
| Records the position and motion of the heart muscle<br />
| Identifies abnormalities in heart muscle such as hypertrophy of ventricles(useful for determining cardiac involvement)<ref name="PMID:2940284"><pubmed>2940284</pubmed></ref>.<br />
| [[File:Echocardiogram concentric left ventricular hypertrophy.jpg|thumb|Echocardiogram concentric left ventricular hypertrophy]] Normal Echocardiogram (video): [http://youtu.be/7TWu0_Gklzo]<br />
|- bgcolor="Azure"<br />
| '''Blood tests'''<br />
| Checks for elevated glucose levels (in the event of diabetes developing) and vitamin E levels as individuals with FRDA often have low Vitamin E serum levels <ref name="PMID:11554913"><pubmed>11554913</pubmed></ref><br />
| Blood tests work to identify any possible complication of FRDA (ie: diabetes) and identifies patients who require vitamin E supplements to increase the body's antioxidant capabilities<ref name="PMID:11554913"><pubmed>11554913</pubmed></ref>.<br />
| [[File:Blood test result for glucose and iron.jpg|thumb|Blood test results for glucose and iron]]<br />
|- bgcolor="Azure"<br />
| '''Magnetic resonance imaging''' (MRI)<br />
| Provide brain and spinal cord images that are useful for ruling out other [[#Glossary|'''neurological''']] conditions and confirming dorsal root degeneration.<br />
| Changes in the dorsal root or related neural structures involved in motor coordination can be monitored and identified with MRI. MRI has also been used to diagnose FRDA before the availability of genetic testing where the thinning of the cervical cord was an indication of neurodegeneration<ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>. In a recent pilot study, the [[#Glossary|'''globus pallidus''']] (involved in motor coordination) was found to improve with iron-chelation treatment using MRI technology<ref name="PMID:21791473"><pubmed>21791473</pubmed></ref>. Another paper found that MRI may be a useful tool in diagnosing FRDA and allows researchers to track neural [[#Glossary|'''atrophy''']]<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>. <br />
|[[File:MRI heart.JPG|thumb|[http://youtu.be/G4dFVeP9Vdo MRI of heart]]]<br />
|- bgcolor="Azure"<br />
| '''Computed tomography scans''' (CT scan)<br />
| CT scans work similarly to the MRI in that it is used as an imaging tool to identify neurodegeneration.<br />
| While CT scans can be used in a similar fashion to MRIs, it has been noted that CT scans only identified mild cerebellar atrophy in advanced patients perhaps due to low CT resolution in the neck<ref name="PMID:2759158"><pubmed>2759158</pubmed></ref>.<br />
|[[File:CT lungcancer.JPG|thumb|[http://www.youtube.com/watch?v=MLg-_fsaHso&feature=youtu.be CT of lung cancer]]]<br />
|- bgcolor="Azure"<br />
| '''Nerve conduction studies''' (NCS)<br />
| Measures the speed with which nerves transmit impulses by using two [[#Glossary|'''electrodes''']] (one to send the impulse and the other to measure the response)<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>.<br />
| Nerve conduction studies determines how far and if neurodegeneration has occurred by analysing amplitude, latency, duration, and conduction. Each item assessed will inform the clinician of the number of nerve fibers activated, integrity of [[#Glossary|'''myelin sheaths''']] or [[#Glossary|'''axonal''']] loss<ref name="PMID:21894276"><pubmed>21894276</pubmed></ref>. FRDA diagnosis may be considered if nerve conduction studies indicates nerve degeneration.<br />
| Nerve conduction test (video): [http://youtu.be/0vpVsgdWcvY]<br />
|- bgcolor="Azure"<br />
| '''Genetic Testing'''<br />
| Screens for mutations in the frataxin gene, either a [[#Glossary|'''repeat expansion''']] or a [[#Glossary|'''point mutation''']].<br />
| FRDA is caused by deficient frataxin levels, which is most commonly caused by a GAA repeat expansion in intron 1 of the frataxin gene, and in some rare cases by a point mutation leading to a defective protein product. Both cases lead to deficient frataxin levels. When FRDA is suspected, a genetic test can be used to confirm the diagnosis.<br />
| Genetic screening (video): [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
|- bgcolor="Azure"<br />
| '''Prenatal Testing'''<br />
| A genetic test of the unborn infant. Cells from the developing child can be obtained through [[#Glossary|'''amniocentesis''']] or from the maternal blood, which can then be subjected to genetic tests.<br />
| Same as in [[#Glossary|'''Genetic Testing''']].<br />
|<br />
|}<br />
<br />
===Prenatal Diagnosis===<br />
<br />
Following the localisation of the frataxin gene to chromosome 9 in 1988, a prenatal test was developed for the first time in 1989 by Wallis ''et al'' (1989) <ref name="PMID:2574535"><pubmed>2574535</pubmed></ref>, who used two closely linked adjacent [[#Glossary|'''DNA markers''']], MCT112 and DR47, in their design of a genetic test. This allowed reliable prenatal diagnosis, a useful step for families at risk as the biochemical causes of FRDA were still unknown at the time.<br />
<br />
However, the informativeness of this first prenatal test was still limited to 10-15% of families, and subsequent research has made the effort to increase this initial informativeness. In 1990, Hanauer ''et al'' <ref name="PMID:1970404"><pubmed>1970404</pubmed></ref> identified two further markers that are even closer to the frataxin gene than the two initially used by Wallis ''et al'' (1989). These markers are D9S15 and D9S5. D9S15 alone provided 40% informativeness and only requires very little DNA, which makes it very suitable for prenatal testing. When combining the two markers, only 20% of the families remained uninformed, and when using all four markers, MCT112, DR47, D9S15 and D9S5, 100% informativeness was achieved. This initially seemed to make prenatal diagnosis of FRDA with 99% accuracy or more possible.<br />
<br />
Nevertheless, refinement of the genetic screens continued, especially after [[#Glossary|'''recombination''']] events were detected in the D9S5-D9S15 markers in 1993 <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, rendering the tests suggested by Hanauer ''et al'' (1990) unreliable. Further markers were suggested by Monros ''et al'' (1995) <ref name="PMID:7659688"><pubmed>7659688</pubmed></ref>, who found an accuracy approaching 100%.<br />
<br />
Once the cause of the gene defect was identified as (most commonly) a repeat expansion of the GAA triplet, this provided a direct approach for molecular diagnosis. [[#Glossary|'''PCR''']] and [[#Glossary|'''Southern Blot''']] can be used to detect and thus quantify the repeat, allowing a reliable diagnosis. PCR is the more reliable tool and only needs small quantities of DNA, which make it particularly suitable for prenatal testing. <ref name="PMID:9742572"><pubmed>9742572</pubmed></ref><br />
<br />
===Postnatal Diagnosis===<br />
<br />
Friedreich's Ataxia (FRDA) is often diagnosed based on presenting clinical symptoms but testing for the gene defect that causes it is taken as a definitive diagnosis. A paper on cardiac evaluation of Friedreich's Ataxia patients found that cardiac evaluation using any of the above cardiac testing techniques was a useful tool to compliment genetic testing in terms for screening for patients who should be tested for Friedreich's Ataxia<ref name="PMID12045843"><pubmed>12045843</pubmed></ref>The table below summarises diagnostic steps prior to and after genetic testing was available.<br />
<br />
{|style= "width:60%; height:100px" align="center" border="0"<br />
|-bgcolor="LightSeaGreen"<br />
| '''Availability of genetic testing'''<br />
| '''Diagnostic symptoms'''<br />
|-bgcolor="Azure"<br />
| '''Prior to genetic testing availability'''<br />
| Only physical signs(eg: Scoliosis) and symptoms(eg: chest pains), age of onset and typical FRDA progression could identify it as FRDA. <ref name="PMID:13872187"><pubmed>13872187</pubmed></ref><br />
|-bgcolor="Azure"<br />
| style="white-space: nowrap" | '''After genetic testing is available'''<br />
| Physical complaints are used in conjunction with genetic testing to confirm FRDA. Due to genetic testing, <ref name="PMID:21315377"><pubmed>21315377</pubmed></ref>it has been discovered that FRDA can occur in individuals older than the typical diagnostic age (first two decades of life<ref name="PMID:19283344"><pubmed>19283344</pubmed></ref>).<br />
|}<br />
<br />
==Treatment==<br />
<br />
<br />
Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. Main cause for the congenital disorder is the mitochondrial gene dysfunction where [[#Glossary | '''Frataxin''']] levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage<ref name="PMID:19305405"><pubmed>19305405</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from '''FRDA''' patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for '''FRDA'''<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.<br />
<br />
<br />
'''Iron-chelation'''<br />
<br />
{|align="right"<br />
|[[File:Role of FXN Gene.jpg|330px|thumb|Role of FXN Gene]]<br />
|}<br />
<br />
Iron [[#Glossary | '''chelations''']] potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the '''Frataxin''' deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential '''chelators''' are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.<br />
<br />
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-'''chelation''' had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated '''frataxin''' gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced.<br />
Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.<br />
<br />
<br />
'''Histone deacetylase inhibitors(HDACI)'''<br />
{|align="Right"<br />
|[[File:Frataxin Protein.png|330px|thumb|Frataxin Protein]]<br />
|}<br />
<br />
<br />
Treatment of '''FRDA''' through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of '''fractin''' restoring to normal range within the nervous system and the heart, restoration of '''fractin''' levels was achieved where acetylisation of '''histones''' at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.<br />
<br />
<br />
Positive effects of '''fractin''' level restoration is signs of decrease in progression of '''FRDA'''. Therapeutic use of HDACI led to the normalization of the genetic expression of '''FRDA''' patients. Support of '''fractin''' level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to '''histones''' without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.<br />
<br />
<br />
'''Antioxidants'''<br />
<br />
The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.<br />
<br />
*Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of '''FRDA'''<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.<br />
<br />
*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.<br />
<br />
<br />
{|align="center"<br />
|[[File:Effect of Frataxin Levels.jpg|550px|thumb|Effect of Frataxin Levels]]<br />
|}<br />
<br />
==Current Research==<br />
<br />
A lot of the current research is looking at the potential of idebone, an iron chelator as a treatment for FRDA: <br />
* A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. <ref name="PMID20697044"><pubmed>20697044</pubmed></ref><br />
* Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. <ref name="PMID21779958"><pubmed>21779958</pubmed></ref><br />
* Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. <ref name="PMID20865357"><pubmed>20865357</pubmed></ref><br />
* Antioxidants and other pharmacological treatments for Friedreich ataxia. <ref name="PMID19821439"><pubmed>19821439</pubmed></ref><br />
<br />
<br />
The following recent publication provides an overview of the current therapeutic perspective:<br />
* New advances in the treatment of Friedreich ataxia: promisses and pitfalls. <ref>W Nachbauer, S Boesch '''New advances in the treatment of Friedreich ataxia: promisses and pitfalls.''' Clinical Investigation: 2011, 1(8);1095-1106.</ref><br />
<br />
<br />
The following papers are looking at evaluation criteria of the disease in children. These can differ to the ones used in adults, which nevertheless is commonly also used for younger ages:<br />
* In children with Friedreich ataxia, muscle and ataxia parameters are associated. <ref name="PMID21574990"><pubmed>21574990</pubmed></ref><br />
* Neurophysiological evaluation in children with Friedreich's ataxia. <ref name="PMID19775837"><pubmed>19775837 </pubmed></ref><br />
<br />
<br />
Furthermore, current research seaks to establish norms in the progression rate of the disease in order to allow accurate assessment and optimised treatment:<br />
* Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. <ref name="PMID20063431"><pubmed>20063431</pubmed></ref><br />
* Review: Evaluating the progression of Friedreich ataxia and its treatment. <ref name="PMID19283349"><pubmed>19283349</pubmed></ref><br />
<br />
<br />
Improvements in genetic counseling for FRDA patients are suggested by this recent study:<br />
* Exploration of transitional life events in individuals with Friedreich ataxia: implications for genetic counseling. <ref name="PMID20979606"><pubmed>20979606</pubmed></ref><br />
<br />
==Related Links==<br />
* [[Neural - Cerebellum Development]] - this page relates the development of the cerebellum, in addition to some of the cellular origins.<br />
<br />
* [[Musculoskeletal System - Abnormalities]] - Details more about scoliosis and other musculoskeletal abnormalities.<br />
<br />
* [[Cardiac Embryology]] - Development of heart<br />
<br />
* [[Magnetic Resonance Imaging]] - More on MRI including imaging.<br />
<br />
==External Links==<br />
Video of Ataxic Gait [http://www.youtube.com/watch?v=CBlrp-Ok38E&feature=related]<br />
<br />
Video of a Positive Babinski Sign - [http://www.youtube.com/watch?v=Jr_Lejj0nOc&feature=related]<br />
<br />
Video of Dysmetria - [http://www.youtube.com/watch?v=jnQcKAYNuyk]<br />
<br />
Video of Hyperreflexia - [http://www.youtube.com/watch?v=3PILgkVKlAg]<br />
<br />
Video of nerve conduction test - [http://youtu.be/0vpVsgdWcvY]<br />
<br />
Video of Electromyograph test - [http://youtu.be/UzbcH16AUzE]<br />
<br />
Video of a normal Echocardiogram - [http://youtu.be/7TWu0_Gklzo]<br />
<br />
Video of an MRI (brain and heart)- Brain:[http://youtu.be/rcRm1MrFE8Q] Heart:[http://youtu.be/G4dFVeP9Vdo]<br />
<br />
Video of CT scan (lung cancer) - [http://youtu.be/MLg-_fsaHso]<br />
<br />
Video of Electrocardiogram (normal) - [http://youtu.be/Q0JMfIVaDUE]<br />
<br />
Video of Genetic Screening - [http://www.youtube.com/watch?v=cGxwsuPhDKI]<br />
<br />
==Glossary==<br />
<br />
[[#Introduction | '''Back to top''']]<br />
<br />
'''Aconitase''' - Is an iron-sulphur protein involved in iron homeostasis<br />
<br />
'''Amniocentesis''' - A procedure by which amniotic fluid is drawn out and tested for chromosomal abnormalities<br />
<br />
'''Apoptosis''' - Programmed cell death.<br />
<br />
'''Ataxic Gait''' - Involves a wide-based stance, lack of muscle coordination, errors in range and force of movement, delay in initiating movement. <br />
<br />
'''Atrophy''' - Involves a decrease and/or wasting of an organ or tissue within the body. <br />
<br />
'''Axon''' - The (usually long) process that transmits signals from the neuron it is connected to.<br />
<br />
'''Cardiac Arrhythmia''' - Abnormal rate or beat of the heart, which can be either fast (tachycardia) or slow (bradycardia). <br />
<br />
'''Carrier''' - An individual who is heterozygous for a recessive trait. Heterozygous carriers of a recessive disease allele are often uneffected.<br />
<br />
'''Cardiomyocytes''' - Specialised muscle cells of the heart<br />
<br />
'''Chelation''' - chemicals that form soluble, complex molecules with certain metal ions, inactivating the ions so that they cannot normally react with other elements or ions... ([http://www.astm.org/ ASTM])<br />
<br />
'''CNS''' - Central Nervous System.<br />
<br />
'''Codon''' - A triplet of nucleotides that specifies an amino acid or a start or stop signal in the genetic code.<br />
<br />
'''Cortical''' - Of or relating to the cortex.<br />
<br />
'''Demyelination''' - The loss of the myelin sheath surrounding an axon. <br />
<br />
'''DNA''' - Deoxyribonucleic Acid <br />
<br />
'''DNA marker''' - a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals, or species.<br />
<br />
'''DNA polymerase''' - An enzyme that catalyses the synthesis of DNA using a DNA template.<br />
<br />
'''Dorsal Nuclei of Clarke''' - A group of interneurons in the spinal cord, which relay proprioceptive information from the PNS to the brain. <br />
<br />
'''DRG''' -Dorsal Root Ganglion.<br />
<br />
'''Dysarthria''' – A motor speech disorder causing slurring of words.<br />
<br />
'''Dysmetria''' – Faulty judgment leads to the inability to perform basic movements, uncoordinated movement results. <br />
<br />
'''Dysphagia''' – Involves difficultly of swallowing food, which can lead to coking of food or water, as well as, aspiration pneumonia. <br />
<br />
'''Electrodes''' - A conductor which emits, controls, or collects the movement of electrons (ie: a current)<br />
<br />
'''Erythropoietin''' - A hormone that stimulates red blood cell production.<br />
<br />
'''Frataxin''' - Mitochondrial protein encoded by the FXN gene in humans<br />
<br />
'''FRDA''' - Friedreich's Ataxia.<br />
<br />
'''Founder event''' - A form of genetic drift. The establishment of a population by a small number of indivduals whose genotypes carry only a fraction of the different kinds of alleles in the parental population.<br />
<br />
'''GAA''' - Guanine Adenine Adenine Nucleotide Triplet.<br />
<br />
'''Gene silencing''' - Inhibition of the gene expression.<br />
<br />
'''Globus pallidus''' - A sub-cortical region of the brain, part of the extrapyramidal motor system.<br />
<br />
'''Grey Matter''' - Contains neural cell bodies which lie in the CNS.<br />
<br />
'''Hematocrit''' - Measures the volume of red blood cells in blood.<br />
<br />
'''Histone''' - A protein around which DNA coils to form chromatin.<br />
<br />
'''Histone deacetylase inhibitors''' - These are compounds that interfere with enzymes that remove an acetyl group from histones.<br />
<br />
'''Heterozygous''' - Possessing two different variants of a gene.<br />
<br />
'''Homeostasis''' - Maintaining a balance or internal equilibrium with in the body.<br />
<br />
'''Homozygous''' - Possessing two identical variants of a gene.<br />
<br />
'''Hyperreflexia''' – Over active reflexes responses, which can lead to spastic movements<br />
<br />
'''Hypertrophy''' - Increasing in size of a organ or tissue.<br />
<br />
'''Hypotonia''' - Decrease in muscle tone. <br />
<br />
'''Intron''' - DNA sequence that lies between coding regions of a gene. Introns are transcribed but are spliced out of the primary RNA product and thus do not contribute to the polypeptide encoded by the gene.<br />
<br />
'''Linkage''' - The condition in which genes have their loci on the same chromosome, causing them to be inherited as a unit, provided they are not separated by crossing over during meiosis. The closer two genes are located two each other on the chromosome, the "tighter" the linkage; the less likelihood there is for them to be separated during meiosis.<br />
<br />
'''Linkage studies''' - exploit the idea that tightly linked genes are inherited together: if the location of one gene is known and it is suspected to be linked to a second gene, this can be used to determine the location of the second gene.<br />
<br />
'''Missense mutation''' - A mutation that alters a codon to that of another amino acid and thus leads to an alteration in the resulting polypeptide.<br />
<br />
'''mRNA''' - Messenger RNA. The product of gene transcription, which will be translated into protein.<br />
<br />
'''Myelin sheath''' - An insulating cover that wraps around individual nerves to increase the speed of conduction.<br />
<br />
'''Neurological''' - Pertaining to the nervous system or nerves.<br />
<br />
'''Neuron''' - The excitable cell of the nervous system. <br />
<br />
'''Nonsense mutation''' - A mutation that creates a stop codon, thus leading to the halt of translation and a shortened gene product.<br />
<br />
'''Oligodendrocytes''' - Are the supporting cells in the CNS.<br />
<br />
'''PCR''' - Polymerase Chain Reaction. A method for amplifying DNA segments.<br />
<br />
'''Periventricular''' - Around or near a ventricle. (A ventricle is an opening or chamber in the body.)<br />
<br />
'''Pes cavus''' - Feet with abnormally high arches.<br />
<br />
'''Phagocytosis''' - The process in which a cell engulfs particles, such as debris.<br />
<br />
'''Phenotype''' - Traits or characteristics that are observable externally.<br />
<br />
'''Pneumonia''' - Inflammatory condition of the lungs. <br />
<br />
'''PNS''' - Peripheral Nervous System.<br />
<br />
'''Point mutation''' - A mutation affecting a single nucleotide.<br />
<br />
'''Positive Babinski Sign''' – The big toe extends up and backward whilst the other toes splay outward (abduct). This is sign of upper motoneuron disease. <br />
<br />
'''Proprioception''' - Refers to the ability of sensing movement and position of muscles without visual guides. Required for hand-eye co-ordination.<br />
<br />
'''Purine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Pyrimidine''' - One of the two chemical classes to which nucleotides belong.<br />
<br />
'''Reactive Oxygen Speices (ROS)''' - It is a classification for chemically-reactive molecules containing oxygen.<br />
<br />
'''Recombination''' - The process that leads to the formation of new gene combinations on chromosomes.<br />
<br />
'''Redox''' - A reversible chemical reaction in which one reaction is an oxidation and the reverse is a reduction.<br />
<br />
'''Replication''' - The process whereby DNA is duplicated.<br />
<br />
'''Scoliosis''' - Abnormal curving of the spine in the Coronal plane to form an 'S-shpe' when viewed from the front.<br />
<br />
'''Schwann Cells''' - Are the supporting cells of the PNS. <br />
<br />
'''Sepsis''' - Infection of the blood, generally bacterial.<br />
<br />
'''Southern Blot''' - A technique in which DNA fragments are separated and transferred to a nylon or nitrocellulose membrane. Specific DNA fragments can be identified by hybridisation to a complementary, radioactively labeled probe.<br />
<br />
'''Splicing''' - The reaction in which introns are removed and exons are joined together in the mRNA molecule.<br />
<br />
'''Tachycardia''' - A resting heart rate that exceeds the normal range.<br />
<br />
'''Triplet repeat (trinucleotide repeat)''' - A tandemly repeated cluster of three nucleotides, such as GAA in FRDA, within or near a gene.<br />
<br />
'''T-wave''' - On an ECG, it represents the recovery of the ventricles.<br />
<br />
==References==<br />
<references/></div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2011_Group_Project_8&diff=76633Talk:2011 Group Project 82011-10-10T06:46:18Z<p>Z3389343: /* Collated Peer Review */</p>
<hr />
<div>[[2011_Group_Project_8|'''Group 8''']]: [[User:z3294943]] | [[User:z3389343]] | [[User:z3329495]] | [[User:z3332250]]<br />
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{{2011GroupDiscussionMH}}<br />
<br />
<br />
'''Page Edits 30 Sep'''<br />
<gallery><br />
File:2011_Project_Group_8_edits.jpg|Project Page<br />
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project<br />
File:2011_Talk_Group_8_edits.jpg|Discussion Page<br />
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion<br />
</gallery><br />
<br />
<br />
==Collated Peer Review==<br />
<br />
Hey guys, here's the Pedigree redrawn with PowerPoint. It's not perfect cause somehow powerpoint didn't always realise I wanted the connecting lines to be horizontal/vertical, so this is the best I could come up with. Let me know what you think!<br />
<br />
[[File:Friedreich's Ataxia Pedigree.png]]<br />
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Yeah i got the permision for that, and sure, i'll change the picture size. i only put them as 200px to fit into their sections. Also cuz it'll flow into neuropathy section...<br />
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YAY! I love the pic of the heart!!! well done, im guessing you got permission amanda??<br />
I think maybe we could put the pic down with complications?? and enlarge the pathogenesis again as i think that pic really describes the path well!! but again they are your sections so totally up to you! <br />
and remember the smallest a pic can be is 240px as thats what it says in the images tute.<br />
and Elina i think the pic you enlarge looks good!<br />
z3294943<br />
<br />
<br />
Hey guys, i've sent out some requests to use images of cardiac hypertrophy but in case we dont get the permission on time i suggest we use the one we've already got? How does everyone feel about that? but all the same, I really hope to get those permissions!<br />
<br />
I just realised that I'm saying in my part that the repeats are up to 600-900 in most FRDA patients, so how about you modify your graph to 6-12 GAA repeats, and then >12 repeats? Then it should be fine and not contradict what I say in any way.<br />
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<br />
I'm utterly confused whether I should put this comment on top or on bottom of the page, but never mind.<br />
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Your graph is fine, it doesn't contradict my information, it's in line with it. I could add that into the information, if you want? Cause I do think we need to explain it a bit more - or at least, I could easily, which would make the graph make more sense. Something along the lines of "it shows that the higher repeat expansions are more prevalent in caucasian populations, which is in line with the increased prevelance of it in those countries", and more. I don't want to sound patronising, it's just I know exactly how I'd explain it. lol<br />
<br />
About referencing the picture: I couldn't find the actual picture, but how I'd reference the website is: '''Wellcome Images.''' (n.d.). Retrieved September XY (whatever the date was you got it), 2011, from http://images.wellcome.ac.uk/<br />
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I made the graph on the gene expression part a bit bigger so that you could actually read some of the information. I was playing around with it a bit, it drags into the next section which doesn't bother me too much, I just tried to not make it drag into too much. The size it has now is kind of a compromise between easily readable and not dragging too much into the next section. What do you think?<br />
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<br />
Hi guys let me know what you think of the graph on the page of the symptoms..<br />
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Im not 100% about the second graph (below) of GAA repeat ELina could you just check it as i think it might contradict your info if so I wont add it in I attached the link to the paper... If you think its ok Elina let me know so I can fix up the referencing etc<br />
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[[File:GAA Frequency in FRDA.jpg|400px|]]<br />
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z3294943<br />
<br />
Hey Amanda, I tried to see if I could fix up the pic but it don't think it looks any better :( so i think on thursday we can decide as a group whether we use it.<br />
Elina could you please try an reference the pic of Friedreich I would hate to lose it! If not let me know and ill give it a go. the reference is in the summary. Thank you!<br />
Also did any of you come across and tables/graphs that I could use in the epidemiology section.. I have been searching like crazy but everything is copyrighted! <br />
<br />
z3294943<br />
<br />
I do have another picture for that section but it needs to be fixed up - i tried fiddling around with contrast/lightness but it didn't get me anywhere. If you could fix it up it'll help heaps! [[File:Heart disection.jpg|thumb]]<br />
<br />
I think we should do our own sections I think it would easier.<br />
Also amanda i think we need another pic in pathology since we have linked the sections it looks a little text heavy are there any cardio pic we could add in??<br />
z3294943 <br />
<br />
Hey, i agree with connecting just the first word that appears to be linked to the glossary. Otherwise we'll take forever to link them all up. and ref 49 might not be appearing due to some issues with the program? maybe ask Mark. I've also emailed him about using screen grabs in the diagnosis table but he hasn't replied yet :( Also is one person linking up the words or are we each linking the words up in our section?<br />
<br />
Hey guys, with connecting the words to the glossary i think we should just do it when the word first appears. let me know what you think!<br />
Also does anyone know how to fix ref 49?? i tried re referencing it but it didn't work??? :(<br />
z3294943<br />
<br />
Intro: <br />
*Positive: Impressive and to the point. Gives good overview of topic.<br />
*To fix: Image reference is not in correct format.<br />
<br />
History<br />
*Positive: Many references which is good to see. Good format of timeline<br />
*To fix: Maybe more info in timeline, Timeline could be better suited into a table.Possibly make image above slightly smaller so that it does not drag into this section. <br />
<br />
Epidemiology<br />
*Positive: This section is impressive. Looks like much research has gone into this section.<br />
*To fix: I think you should put the headings on a separate line above the information and add some pictures. Expand on 'Distribution,' 'Populations,' and 'Gender<br />
<br />
Neuropathology<br />
*Positive: I can see a lot of effort in there from content to the drawn images. This section is impressive! It is very detailed. Good balance of images and text. Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work. Really good content, and nice flow. Very applicable to the audience.<br />
<br />
*To fix: A description of the image "Cross section of the spiral cord" would be good. Great self-drawn images, however could you possibly further describe what the images are depicting. Connect neuropathology and pathology<br />
<br />
==Peer Review==<br />
<br />
'''Group 8 Review'''<br />
*Introduction – some sentences need commas, just check this. Otherwise excellent intro. <br />
*History – the timeline in a table has looked good in other project pages, I suggest you use this too as it will just break it up nicely and add some colour. Especially with the Epidemiology being in a very similar format below, it will just help to differentiate and make it super clear between the sections. <br />
*Epidemiology – the wheelchair age, do you mean, by 45, 95% of people are wheelchair bound? What is the most common age? Just need to make this point clear. <br />
*Pathogenesis – is there any other things to talk about other than cardiomyopathy? Or is ‘Neuropathology’ meant to just be a subheading, not a title? Make sure all technical terms in the neuropathology section are defined, as neuro can be confusing and complicated. <br />
*Need a description of the spinal cord cross section, try and link it in to what is written in the text<br />
*Symptoms paragraph – can you divide this up into 2 paras if poss? Just looks like a big slab of text and therefore is hard to read, especially as the writing as been smushed up from the pictures. <br />
*Diagnostic table – don’t forget to complete the last column! Try and have a bit more space between it and the Prenatal diagnosis section below it, would look better. <br />
*Current research – would look better if you described the findings of the paper and made the title of the paper in bold – some other groups have done this really well. <br />
*Otherwise, good project!<br />
<br />
--[[User:Z3332824|z3332824]] 14:49, 29 September 2011 (EST)<br />
<br />
Group 8: <br />
Incredible work on the page. A balance between the text and images is greatly seen. <br />
The size of the image between history and introduction is quite big. Minimize it and place it in the right section. <br />
Epidemiology can be transferred into a column chart to see which one is more prevalent. <br />
Images in the Aetiology section are phenomenal but you want to make the drawings darker? Since they appear to be fading. <br />
Neuropathy section is spectacular. I can see a lot of effort in there from content to the drawn images. And I liked how in the table of diagnosis, the use of external links to deliver the information better. Finally, one of the references need to be reformatted as it refers to nothing (49) and the Gloassary could be shifted to be above the reference list. <br />
--[[User:Z3284061|z3284061]] 11:52, 29 September 2011 (EST)<br />
<br />
'''Peer Assessment'''<br />
<br />
* Overall the project is very good<br />
* Maybe more info in timeline<br />
* A description of the image "Cross section of the spiral cord" would be good<br />
* Good balance of text/image/tables<br />
* No dates are mentioned in the current research<br />
* Good use of student image<br />
--[[User:Z3292953|z3292953]] 11:06, 29 September 2011 (EST)<br />
<br />
<br />
'''''Friedreich’s Ataxia (Group 8) Peer Review:'''''<br />
<br />
Why is there a massive gap at the beginning? <br />
<br />
Introduction: Impressive and to the point. Gives good overview of topic. Image reference is not in correct format. <br />
<br />
History: Possibly make image above slightly smaller so that it does not drag into this section. Many references which is good to see. Good format of timeline. <br />
<br />
Epidemiology: This section is impressive. Looks like much research has gone into this section. <br />
<br />
Aetiology: Extensive information which is good. Could you make the self-drawn images a bit darker? Last image lacks student template. Good use of subheadings to organize information. <br />
<br />
Pathogenesis: This section is good, however if possible it could be further elaborated. Image in this section is very nice, although is lacking a student template. <br />
<br />
Neuropathology: This section is impressive! It is very detailed. Good balance of images and text. Great self-drawn images, however could you possibly further describe what the images are depicting? Otherwise, well done. <br />
<br />
Clinical Presentation: Content is good. Images could be spaced out a bit more. <br />
<br />
Diagnosis: This section is also impressive. Very detailed and great use of tables. Could you add more images into the relevant sections of the table? <br />
<br />
Treatment: Information is good, however at the moment it looks like a slab of information. Possibly balance it out with some images. <br />
<br />
Current Research: Many references which is good. Once again, an image would be good.<br />
<br />
Glossary and references are good, however place the glossary before the references. <br />
<br />
Overall, good job! --[[User:Z3290808|z3290808]] 10:48, 29 September 2011 (EST)<br />
<br />
<br />
Friedrich’s Ataxia – Group 8<br />
<br />
* Introduction well written. Good use of image and referenced well. <br />
* Timeline looks good. Is it a little short? Maybe there are some more events that you could include. The use of a table here could be good to summarize the timeline and center it. <br />
* Epidemiology seems to cover all the information required. I thought an image in this section could look nice.<br />
* Aetiology is highly detailed and well written. Subheadings help to give it more flow, but it is still very text heavy. Is there a way to incorporate a table or perhaps some dot points under some of these headings to make it a little more concise? <br />
* I thought pathogenesis was wall written, however not much is mentioned on the pathophysiology of the syndrome. This could be elaborated on and more detail given about the development. Good image in this section.<br />
* Neuropathology is very well written with excellent use of images. I though maybe a review of the formatting could improve this section just to give it a little more flow. Good use of dot points in this section. <br />
* Clinical presentation and diagnosis look excellent. <br />
* Treatment section is very text heavy, this could be improved with the use of an image and maybe a table to summarize the info. <br />
* Current research is a good start. Not much elaboration as to what this current research actually achieves though. I thought that a mention of future research prospects could improve this section <br />
* Glossary looks great and reasonably complete. <br />
* Overall this was a very good project. Just some improvements in formatting, inclusion of a few more images and work on the overall consistency of writing (i.e detailed in some sections, and a lot less in others) would improve it I think. <br />
<br />
--[[User:Z3288196|Z3288196]] 10:46, 29 September 2011 (EST)<br />
<br />
<br />
Group 8:<br />
<br />
Glossary is extremely long probably because the words are supposed to be explained in the text. The text is very heavy and the no. of pics drops off towards the end and gets gradually less attractive. Even though there are a few pictures at the top, they are very small and hard to see. <br />
<br />
Its very long and that reflects the amount of effort and reading done. Summarise a little more? Cut down and make it specific. <br />
<br />
Current research seems a little patchy and incomplete. Was the dot points on purpose?<br />
<br />
z3332178 =]<br />
<br />
<br />
'''Peer Assessment'''<br />
*Introduction and History: well written. Maybe place the image in the history section rather than in introduction. The timeline should be expanded a little. It might be a good idea to include more information on other key events in the paragraph above the timeline which at the moment only includes information about Friedreich. <br />
*Need to summarize the information in etiology section more. It's very text heavy and difficult to follow. Strongly suggest the student drawn images in this section be redrawn using word, power point or paint. <br />
*Hyperlink words to the glossary. Makes it much more user friendly.<br />
*Pathogenesis: well written. Not sure if neuropathology needs to be a different section from pathology. <br />
*Other sections; good job! Good use of tables and images to present the information. <br />
*Try to incorporate a table in the treatment section. Looks a bit mundane compared to the other sections.<br />
*The double spacing in the 'current research' section looks awkward. Need to fix the layout of this section.<br />
*Overall, good job! <br />
--[[User:Z3291622|Z3291622]] 10:28, 29 September 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
This wiki looks like a lot of time and effort has been invested into the project and very nicely done. There is an abundance of referencing and loads of info given that this was one of the lowest reference item found in BioMed website. You've also used the correct referencing programming so it doesn't repeat. Bravo!<br />
<br />
:*It is a marathon to get passed all of this. It is text heavy, though it is hard to deny that all info is relevant.<br />
<br />
:*Aetiology's images aren't done too well. It hasn't translated as well when viewing it from the wiki as it is very faded and overall feels rushed in making. Use Paint is my recommendation.<br />
<br />
:*Timeline could be better suited into a table.<br />
<br />
:*All student drawn images aren't referenced properly. Just missing the disclaimer and the inspiration from info.<br />
<br />
:*The first dot point of The Spinocerebellar Tract seems out of place, don't quote. Hypotonia's dot point in explaining the definition is longer than the glossary definition.<br />
<br />
--[[User:Z3293267|z3293267]] 10:03, 29 September 2011 (EST)<br />
<br />
*intro: maybe move the image into the history section<br />
<br />
*history: perhaps putting it into a timeline would look better.<br />
<br />
*research: could have briefly summarised a bit of what the articles were about<br />
<br />
*student drawn image had no reference and is a little light on colour.<br />
<br />
*external links were great <br />
<br />
--[[User:Z3290558|z3290558]] 10:00, 29 September 2011 (EST)<br />
<br />
Peer Review<br />
<br />
Some places for improvement. <br />
<br />
:*Double spacing of paragraphs looks awkward.<br />
<br />
:*History section would benefit by placing the information into the timeline rather than paragraphs as it is a bit hard to follow. Could also be expanded.<br />
<br />
:*In the epidemiology section the subheadings do not present the information in the best way possible. It makes it look like there is a lack of research into this area. Perhaps combining into paragraphs, or adding more information to each subheading. <br />
<br />
:*The pathogenesis section needs some additional information.<br />
<br />
:*Further explanation of terms in the symptoms section is needed as the web page is aimed at those that may not have a clinical knowledge. <br />
<br />
:*Research could be summarised and papers talked about rather than just listing papers of current research.<br />
<br />
:*Glossary is extensive but would be more appropriate following the information on the page rather than after the references as it gets forgotten about.<br />
<br />
:*References need to be fixed. There are many that are just a web address. Full citation is needed. Double ups need to be fixed.<br />
<br />
--[[User:Z3217043|z3217043]] 09:51, 29 September 2011 (EST)<br />
<br />
Group 8 Peer Review<br />
<br />
*The headings are well chosen and ordered<br />
*Epidemiology-well done<br />
*Student drawings need to be more defined<br />
*The gene expression image could be larger<br />
*All the images are on the right side of the page-you could reformat a little to make it a bit more interesting<br />
*Little confusing between main headings and subheadings under aetiology-just an issue of font size or bolding<br />
*External links-really good<br />
*Glossary was great however could be placed before referencing-at first wasn’t sure if it was present as it was at the end<br />
*Well referenced<br />
--[[User:Z3308965|Fleur McGregor]] 09:34, 29 September 2011 (EST)<br />
<br />
<br />
Group 8<br />
<br />
*Great intro, very succinct, and great history. Timeline could be formatted into a table, if you want, doesn’t really matter. Information is well referenced.<br />
*Aetiology – image is difficult to see, maybe use a black marker or felt tip. Bold text corresponds with glossary which is great, maybe you could go a step further and link the words to the glossary. Evidence of extensive research, gooooood job.<br />
*Neuropathology is a well researched section, great formatting and very well structure paragraphs, great work.<br />
*Table under ‘Clinical Presentation’ could have clearer borders, along with the table under ‘Diagnostic Tools’ and ‘Postnatal Diagnosis’<br />
*Great work on the glossary, really extensive and most terms are included<br />
<br />
--[[User:Z3331469|z3331469]] 08:12, 29 September 2011 (EST)<br />
<br />
GROUP 8: Friedreich’s Ataxia<br />
*Contenets section not visible<br />
*Info in both intro and history is very cohesive and informative, however, i feel the timeline could use a bit more work, there's large gaps in between dates (did anything happen in between these dates?) also it would be good if it also included fairly recent advances<br />
*Epidemiology has been sectioned well, info is informative, however, it could be better if it was in the form of a table<br />
*The chromosome image is a little faded and not really easy to see, could you maybe fix this so it's clearer <br />
*Aetiology has been researched well, subheadings are suitable and fit in well, good balance of text and images, info is detailed and understandable, however, some sections could use more referencing (Genetic Instability & Inheritance particularly)<br />
*Again the pedigree student drawn image could be a little more clearer <br />
*The Gene expression responses of Friedreich's ataxia image needs to be referenced properly and student template should be added <br />
*Pathogenesis image could use a more informative legend<br />
*Pathogenesis has concise and understandable info, the subheading Cardiomyopathy could be also included in glossary as some may not know what this is <br />
*some words in Neuropathology need explaining in the glossary e.g. neuropathological, dorsal nuclei of Clarke, Schwann cells, oligodendrocyte etc.)<br />
*A better description of the spinal cord image is needed<br />
*Neuropathology has been research extensively and info is very informative and well explained, however, more referencing may be needed <br />
*some of the info at the beginning of Clinical Presentation could be better as part of the history section<br />
*Table in this section could be defined a little more with boundaries to differentiate one section form another<br />
*Current research could be expanded on more by explaining the findings not just lists and links<br />
<br />
Overall:<br />
*very good structuring of headings and subheadings<br />
*Glossary seems fine, words could be linked to the glossary as an improvement so the reader doesn't have to be scrolling down, some words could use more explaining (e.g. DRG, CNS etc.)<br />
*Student drawn images could be clearer and some images need to be referenced properly<br />
*good use of external links<br />
*tables could be formatted better (better defined boundaries) <br />
*good balance between text and images throughout most of page<br />
<br />
--[[User:Z3331556|z3331556]] 07:39, 29 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Peer Review'''<br />
<br />
• Good overall layout and effective sub-heading structure. Your images are really useful, however I feel there is a lot more text than there is images.<br />
<br />
• Introduction and history are really good! It’s a good opening to the page, and very interesting abnormality. Obviously, well researched. Could the timeline be expanded?<br />
<br />
• Epidemiology is also really good, however the addition of a table or graph could really compliment this information.<br />
<br />
• Aetiology has good content, and I like how you’ve emphasised important terms by highlighting them. This would look better if it was consistent throughout the entire page.<br />
<br />
• Pathogenesis is a good start, but I think it needs more detail. Really good diagram though!<br />
<br />
• Neuropathology has been done really well! Really good content, and nice flow. Very applicable to the audience.<br />
<br />
• I like the use of the table in the diagnostics section. (Nice consistency of the colour of tables). <br />
<br />
• Current research could maybe be broken down into headings and then brief summaries of each paper under each heading. <br />
<br />
• Nice range of external links! Could they be incorporated into their relevant subheadings?<br />
<br />
--[[User:Z3289829|z3289829]] 02:46, 29 September 2011 (EST)<br />
<br />
<br />
*Introduction: Good introduction, gives an overall image. Quite like the image.<br />
History: I don’t think history of the guy who found it is that necessary, perhaps just focus on the disease itself. Only 5 events in timeline? Surely there’s more after 1996.<br />
<br />
*Epidemiology:<br />
Love the subheadings and the straight-to-the-point approach instead of writing paragraphs describing something that could be said in one dot point. The content is exactly what the epidemiology should cover.<br />
<br />
*Aetiology: image is unclear and looks like it was done in a rush. Where’s the referencing? hThe information is very informative however and quite good use of subheadings, but it would be improved by bolding a few of the significant words.“Friedreich's Ataxia Pedigree.jpg” not referenced correctly.<br />
<br />
*Pathogenesis: Love the image, very clear and concise.<br />
<br />
*Neuropathology: VERY detailed and word-heavy. It shows you’ve done the research but it’s too much to read and become boring after a certain point. You can summarise some of the sections quite easily.<br />
<br />
*Clinical: Great content, and fantastic use of subheadings.<br />
<br />
*Diagnosis: fantastic formatting for the tables. <br />
<br />
*Treatments: Need an image of some sort here, but the information is very relative. <br />
<br />
*Glossary: Needs to be placed before the reference list.<br />
<br />
*References: Looks good, couldn’t find any mistakes.<br />
<br />
*Image/Text ratio: Some parts the text is too long and need a picture to break it up and in others it just plain needs an image to make it interesting,a s mentioned above.<br />
<br />
--[[User:Z3290270|z3290270]] 02:24, 29 September 2011 (EST)<br />
<br />
<br />
'''Peer Review'''<br />
* Good balance between text and pictures; inclusion of self-drawn pictures is noted.<br />
* The Introduction gives a very good broad overview of the topic, properly referenced, without impinging on the information presented later.<br />
* The History presented is made relevant to the understanding and treatment of the disease.<br />
* Appropriate subheadings are used in the Epidemiology section and the text is succinct, makes things more understandable. Well referenced. Similar story with Aetiology - the inclusion of pictures works well, as each is fairly relevant.<br />
* To be honest, it's really just good overall. There's nothing that needs fixing, in my view....<br />
--[[User:Z3290689|z3290689]] 02:09, 29 September 2011 (EST)<br />
<br />
<br />
Group 8: Friedreich’s Ataxia<br />
*Overall: Well done on headings/sub headings and consistent formatting. Well balanced in terms of text and imagery.<br />
*Introduction: brief, concise and captivating. Good start to the webpage.<br />
*History: I like the addition of a timeline – always a nice touch to summarise history of disease<br />
*Aetiology: Well done with those hand drawings, but definitely need to be darker<br />
*Neuropathology: evidently a well researched and presented section. Referencing is good and reinforces reliability of information provided. Well done<br />
*Diagnosis: good use of table, but some sections are too wordy<br />
*Current Research: well referenced but the bullet points make the section look incomplete. Consider using paragraphs or adding more information.<br />
--[[User:Z3332327|z3332327]] 01:21, 29 September 2011 (EST)<br />
<br />
Peer review of group 8: <br />
<br />
*Introduction is good, short and succinct.<br />
*the timeline in history could be in a table to make it stand out a bit more and break up the text.<br />
*how about subheadings be used instead of bolded words<br />
*no copyright statement on both drawn images<br />
*pathogenesis could be very heavily expanded, this is the biggest part of your project so spend some more time on it.<br />
*no copyright notice on the student drawn image in neuropathology.<br />
*how about a table or dot points for clinical presentation to make it more easier to read.<br />
*email copyright assurances from the video owners to embed into your table for diagnosis?<br />
*elaborate a bit upon the current research section to give an image of what is happening now!<br />
*multiple references present.<br />
--[[User:Z3291423|Jasjit Walia]] 23:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Peer Review for Group 8'''<br />
<br />
* Nice picture of Friedrich which is found in a good introduction to the disease.<br />
* Timeline seems short, try to expand on it as there is a massive time gap from 1907 to 1988<br />
* I like the way you separated your info under epidemiology into sections which makes it easier to read. Also isn’t there any graph you may be able to show in this section?<br />
* Hand drawn image of the chromosome needs to be referenced properly in accordance to student author referencing as outlined in editing basics.<br />
* Information in the inheritance section under aetiology has no referencing to it, please insert it if its missing.<br />
* In the pathogenesis a link to the word Neuropathology should be made so it can show the reader where it is.<br />
* Under Neuropathology the image of the spinal cord cross section should have a description added to it so it can explain to readers the importance of this image.<br />
*In the middle of the section under Dorsal Root Ganglia, a definition of a Schwann cell was given. You can remove this and instead added it to the glossary as this sentence disrupts the flow of the paragraph.<br />
* First paragraph under spinocerebellar tract has to references to the information.<br />
* Under each section for the neuropathology, you give a description, then the abnormality found in the ataxia. If you put little subheadings such as ‘description’ and ‘abnormality in F.ataxia’ it will organize your page much better.<br />
* in the symptoms section, put a hyperlink to the word ‘diagnosis’ as it will direct the reader to that section on the page.<br />
* Bullet points should be used for the info in the table under the symptoms section<br />
* Under complications, I don’t think reactive oxygen species needs capital letters.<br />
*table used under the Diagnostic tools section is well constructed and informative, well done.<br />
*current research section could be improved by providing dates and descriptions of each bullet point. It will provide the reader a good image on the type of current research that is occurring for this ataxia.<br />
* referencing is good, well done.<br />
*External links section is good, maybe expand It a little bit more as it would look better.<br />
* Glossary is well done, and I like the way you highlighted words in your page that have their definitions in the glossary.<br />
<br />
--[[User:Z3291317|Z3291317]] 23:51, 28 September 2011 (EST)<br />
<br />
Group 8<br />
Hey, well done, your page is looking really polished! Lots of very interesting information here and presented in a very easy to follow manner<br />
<br />
#The key points relating to the topic that your group allocated are clearly described. <br />
#* History: I feel that you could lessen the info of Nicholas and add more current findings of the disease.<br />
#* Aetiology: What is the chromosome 9 image based on? Need to work on referencing. Very good subheadings and well balanced with images<br />
#* Pathogenesis: Needs more information<br />
#* Neuro: What's the images based on? Good subheadings and explained well. I liked the way you gave explanations for normal function/appearance and then went on to explain abnormality associated with the structures in this disease. But you need to improve your referencing for this section<br />
#* Diagnosis: Very good table and images. But need to fix the postnal diagnosis table so that it spans the length of the screen<br />
#* Symptoms: table and images look too crowded<br />
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area. <br />
#* good subheadings, images, impressive self drawn images! Nice balanced page layout<br />
#Content is correctly cited and referenced.<br />
#* needs to work on referencing<br />
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.<br />
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities. <br />
#* research done is evident, just need to reference<br />
#Relates the topic and content of the Wiki entry to learning aims of embryology. <br />
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki. <br />
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement. <br />
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning. <br />
#Develops and edits the wiki entries in accordance with the above guidelines<br />
<br />
"What would improve this project...." <br />
<br />
* referencing<br />
* better arrangement of table and images so page doesn't look too crowded<br />
<br />
Well done guys, nice team work!<br />
--[[User:Z3291643|z3291643]] 23:48, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
History: Timeline could be more detailed.<br />
<br />
Epidemiology: I think you should put the headings on a separate line above the information and add some pictures.<br />
<br />
Aetiology: This section is very detailed but the pictures are difficult to see. They need to be bigger but some of the hand drawn ones need darker text and more detailed captions.<br />
<br />
Pathogenesis: Great diagrams. Looks really good with lots of pictures. Well explained. The diagrams could be a bit bigger though.<br />
<br />
Symptoms and diagnosis: Good information but could be organised more neatly. The table looks like it has a lot of text and not enough pictures.<br />
<br />
Treatment: needs some pictures to balance out the text<br />
<br />
Current research: This section needs more detail. It would be better in paragraphs not dot points.<br />
<br />
--[[User:Z3291324|z3291324]] 23:25, 28 September 2011 (EST)<br />
'''Group 8:'''<br />
<br />
•Good job on the introduction and history, concise and easy to read. Also the image here is also good to break up the text.<br />
<br />
•The timeline seems a little short however, is there anything else you can add after 1996?<br />
<br />
•Make sure that all of the student drawn images have the correct copyright information. You need to make sure you have the correct template in the information for all of these images.<br />
<br />
•I like the fact that you have bolded some of the words included in the reference but this isn’t consistent throughout all sections. This needs to be completed for all sections and all terms included in the glossary.<br />
<br />
•Also, maybe incorporate some of the external links into the relevant sections throughout the page if possible.<br />
<br />
•The references should be the last thing, underneath the glossary and external links <br />
<br />
•Overall well researched and it seems to be well written, just some formatting and consistency problems, but good job so far.<br />
<br />
--[[User:Z3332183|z3332183]] 21:32, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8: Peer Assessment'''<br />
* Overall you page is well structured, has relevant content and is written nicely. It also fits nicely together, good group work.<br />
* May be you could put a picture of a person with this disorder in?<br />
* Structure and content of the introduction and history is good. What happened between 1907 and 1988?<br />
* Good use of subheadings in the epidemiology section<br />
* You aetiology section is informative and nicely balanced<br />
* "The fraxtaxin gene on chromosome 9": can you get a better contrast for that image?<br />
* The aetiology, neuropathology, clinical presentations and diagnosis sections are all well written, interesting and have the right amount of text and images<br />
* The current research section looks rather unfinished in comparison to the rest. May be you can put the information into a few paragraphs instead of bullet points.<br />
* The current research section is interesting, just lacks dates<br />
* Glossary, References and External links are fine --z3279511 17:13, 28 September 2011 (EST)<br />
<br />
<br />
''' Group 8 peer review'''<br />
* Introduction and History are well presented, and structured well. It's quite easy to read. The history section could perhaps have a little bit more substance, and your findings end around 1996; does this mean that there has been nothing done since 1996? What is the situation now? It's also slightly lacking in the time period between 1907-1988; surely some significant discoveries would have been made in this period.<br />
* Epidemiology is well structured and covers all aspects of epidemiology. Perhaps a graph or table will structure the information slightly better, but otherwise, good.<br />
* '''Protect your student-drawn image''' with the copyright statement, unless you're happy to let it go around! The subheadings in the aetiology section are appropriate and the bold words make it easy to read. The images help break up text and this section is very well outlined. <br />
* Perhaps a little more could be written on the pathogenesis section? After all, this is the section where you can take the time to discuss the disease process and how it manifests itself into the form which presents with the condition in the clinic. Therefore, just a little bit more? Try explaining how it affects normal physiology (since patho- (disease) -physiology (normal function)); how disease state alters normal function.<br />
* Excellent Neuropathology section with imaging and referencing all well outlined. The previously mentioned point about the pathophysiology section has to just refer to the neuropathology section to see how it is done!<br />
* Clinical presentation is well set out with the tables used to break up the information. Diagrams and tables in the diagnosis section still require linking to the videos? Perhaps get an image snapshot of the video and link through there.<br />
* Treatment section would be better with a diagram, otherwise it is adequate<br />
* Current research doesn't really give me any dates as to the information, but otherwise is set out well. <br />
* Reference section is extensive and well done - consider putting the glossary before the reference section to make it more accessible.<br />
--[[User:Z3288827|Leonard Tiong]] 12:51, 28 September 2011 (EST)<br />
<br />
'''Group 8'''<br />
<br />
*Good introduction<br />
*I find it hard to believe that you have only found 5 significant findings to put in your timeline, it should also more recent findings <br />
*Good epidemiology<br />
*There is a lot of information in etiology- although the subheadings are good try and think of a way to break up the text<br />
(For further detail on the mechanisms of replication slippage, see Viguera et al (2001) is unnecessary<br />
*Postnatal diagnosis table also seems a little unnecessary <br />
*Treatment needs an image<br />
*Current research should be explained <br />
*Not sure why you put your glossary under your references but this should be the other way around so the reader can easily access the glossary<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The index should be on the left side<br />
<br />
*Introduction: contend is fine, but could be a little more general<br />
<br />
*History: is there mo important milestone after 1996?<br />
<br />
*Epidemiology: the first two subheadings could have more contend, the others are well done <br />
<br />
*Aetiology: well done, good structure and contend, but the chromosome image could have been done with more effort<br />
<br />
*Pathogenesis: looks good<br />
<br />
*Neuropathology: well done, very nice drawings<br />
<br />
*Clinical Presentation: good contend, but more subheadings to break up the text would look better<br />
<br />
*Diagnosis: very well done<br />
<br />
*Treatment: well done<br />
<br />
*Research: should be more detailed contend<br />
<br />
*The Glossary should be placed before the references<br />
--[[User:Z3387190|Z3387190]] 22:37, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8'''<br />
<br />
*The introduction had a nice flow, maybe fix the image on the side for better formatting<br />
*A suggestion would be to expand on the timeline because it is quite brief.<br />
*The use of sub-headings do make it easier to read but it looks not appealing because the information after the sub-headings seem too short. Maybe include a graph!<br />
*Aetiology is not referenced well even though there's so much information there.<br />
* Neuropathology section is too long and i wonder is it really needed too this much of an extent.<br />
*Use of tables is good and well written<br />
*The current research section is short and easy to read. It is nice to see that each point is referenced.<br />
<br />
--[[User:Z3330313|z3330313]] 00:33, 29 September 2011 (EST)<br />
<br />
<br />
===Comments on Group Project===<br />
'''Strengths:'''<br />
*Smooth flow to the page due to good placements of headings, subheadings and subsubheadings.<br />
*The referencing is well-done with correct formatting and there seemed to be no duplication.<br />
*The external links section is good.<br />
'''Weaknesses:'''<br />
*There are some inconsistencies in formatting. <br />
*Some of the images do not come with descriptions and copyright statements allowing wikiusers to use images, especially for student drawn ones.<br />
'''Specific corrections:'''<br />
*Maybe include “frataxin” in the glossary?<br />
*Reference 38 is missing.<br />
*The image on the frataxin gene is a bit faint, maybe it would be better to make the outline darker?<br />
<br />
--Z3389806 06:25, 27 September 2011 (EST)<br />
<br />
<br />
'''Group 8 Critique'''<br />
<br />
#• Epidemiologic figures should not be included in the introduction. Also, neither should pathogenesis. Maybe just explain very simply what the condition is and explain the genes in the pathogenesis. The introduction should be organised a little better.<br />
#• The history is rather short. You need to explain in a little more detail how the disease was discovered, and don’t mention pathogenesis or gene function.<br />
#• The epidemiology is ok<br />
#• Aetiology is fine. Good use of images to support your points<br />
#• Pathogenesis should include the sentences on genes found in the introduction<br />
#• Neuropathology is good, but you need to explain the image of the cross section of the spinal cord<br />
#• Clinical presentation is quite good<br />
#• Diagnosis is very good. Your tables in this section are excellent. Good use of images<br />
#• Treatment and Current Research is very good.<br />
#• Glossary is fine<br />
<br />
--[[User:Z3289991|Robert Klein]] 16:05, 26 September 2011 (EST)<br />
<br />
'''Peer Assessment Group 8-Friedreich's Ataxia'''<br />
<br />
*I am sure you will fix the big gap at the beginning of the page where the contents are supposed to be<br />
*While the introducton is good with relevant information, the paragraph is too long.Maybe consider breaking it into two paragraphs.<br />
*The history section is repititive of the actual timeline. All the information under history could be summarized to incorporate in the timeline. <br />
*The timeline needs further information of what has happened since 1996<br />
*I like how you have the different sections within 'Epidemiology' highlighted. Only improvement you could make is maybe expand on 'Distribution,' 'Populations,' and 'Gender'.<br />
*'Aetiology' has a good balance of interesting information, referencing and pictures. <br />
* The image 'The frataxin gene on chromosome 9' has very poor resolution and missing the copyright information. The description could be a bit more detailed too<br />
*The image 'Cross Section of the Spinal Cord' is missing a description.<br />
*There are a number of student drawn images which is relevant to the section and makes the page look quite original<br />
*The table under 'Diagnosis' is well done and informative<br />
*The 'Current Research Section' will look better as paragraphs rather than bullet points.<br />
<br />
<br />
'''Friedreich's Ataxia'''<br />
<br />
*Where did the contents go?<br />
*Try splitting the introduction up into a few paragraphs as opposed to just the one<br />
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more<br />
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'<br />
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read<br />
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good<br />
*Diagnosis looks fantastic, very nicely set out and lots of interesting information<br />
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare<br />
*Can you expand 'Current Research' a bit, explain what and how they do the research etc<br />
*No glossary?<br />
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read<br />
*'Glossary' will fit better before the references<br />
<br />
<br />
Group 8<br />
* Glossary under the references? This needs to be moved up so people can actually find it<br />
* Good introduction. Gives the background and information that is needed<br />
* History is very short. I believe there is more research after 1996 and what you have supplied is very limited<br />
* Epidemiology is great. I like how you divided it up in sections! Easy to read and gauge the spectrum of the condition<br />
* ‘(For further detail on the mechanisms of replication slippage, see Viguera et al (2001)’ This is not necessary<br />
* etiology is very detailed! Maybe think of ways to break up the text for the reader. The subheadings are great but there is just A LOT to get through<br />
* the diagnosis is great<br />
* postnatal diagnosis- I don’t really understand why you need the table here<br />
* treatment could do with an image. Other than that its really good information<br />
* current research should not be a list. It should shed light on what is to come and the significance of current research- not just a list of papers published recently<br />
<br />
'''Group 8 Assessment'''<br />
*Kind of random, but I noticed all the pictures are formatted the same exact way and on the right hand side. It might be good to switch some of them around just so it looks more appealing and not cluttered. <br />
*Great job of linking the same resource to the same reference number in the reference section. <br />
*Good job of condensing down the timeline into a few major incidents. Maybe consider compiling them into a chart? <br />
*The diagnostic tests chart was impeccable! Superb job on it. My only concern are the videos and whether or not they need better referencing. <br />
*Only parts I saw that needed more referencing were: the Cerebellum and the symptoms chart. <br />
*This is the best referencing job I have noticed thus far. Great job!!! <br />
Only real negative comment is that it looks kind of jumbled and very wordy. Maybe separating things out into charts and bullet points would help to fix this problem… <br />
*Glossary would also probably look a bit more organized if it were a bullet list. Also, do the definitions need to have references also? <br />
*Might be a good idea to also have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. Good job at least bolding them though! <br />
*Great job guys! Just a few formatting things and some referencing and you should be good to go.<br />
--[[User:Z3391078|Z3391078]] 16:14, 27 September 2011 (EST)<br />
<br />
<br />
'''Peer Assessment: Group Project 8'''<br />
*The contents would be improved by being placed on the left hand side of the page.<br />
*Introduction and history are clear and concise.<br />
*The information on etiology could be put in a table to increase the viewer's ease of reading.<br />
*The sections on aetiology, neuropathology, clinical presentations and diagnosis are well written, formatted and have a good balance between images and text.<br />
*The hand drawn images are clear and add to the text.<br />
*In current research more of a summary of the papers and their findings would make the section more informative, as it is unknown what some of the papers are even about: "New advances in the treatment of Friedreich ataxia: promisses and pitfalls." What are these 'promises' and 'pitfalls'?<br />
*The glossary and external links sections could be moved higher up, prior to the references as the references denote the end of the page.<br />
*Overall this project provides a large amount of knowledge for the reader on Friedreich ataxia. It is obviously well researched and thoughtfully formatted.<br />
--[[User:Z3217345|z3217345]] 09:56, 28 September 2011 (EST)<br />
<br />
<br />
'''Group 8:'''<br />
* Introduction: gives a very good, short and broad overview of the disease and links nicely with the history which is also very informative. These sections are very easy to read and I like how the picture connects the two sections furthermore. <br />
* Epidemiology is well researched and covers all aspects. It could benefit from the use of a table or graph to break up the text but otherwise this is a very good section.<br />
* Etiology: Student drawn image needs to include proper referencing and it is a little hard to see; maybe you could fiddle with the contrast or go over it with a sharpie. A few mistakes noticed; Is this meant to be ‘some’, “In <font color=red>same</font> cases, this...”?, “As already <font color=red>mentionned</font>,” and “...investigated in mouse <font color=red>embroys</font>,” so make sure that this section is proof read. Overall this section is very good and extensive. <br />
* Pathogenesis is done well, great image to balance out text.<br />
* Neuropathology: Very impressive student drawn images, although, some need more of an explanation of the drawing. This images compliment the well researched text very well. Good job!<br />
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention. <br />
* Diagnosis: Very impressive table, it is easy to read and not cluttered with too much text, I like the colour choice and I love the use of images and videos – it really consolidates everything. It is good that the table under postnatal diagnosis matches the colour scheme of the one above as it creates cohesion, however, it would look better centred in my opinion. <br />
* Treatment: Very good<br />
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete. <br />
<br />
--z3290815 08:49, 29 September 2011 (EST)<br />
<br />
==Discussion==<br />
<br />
--[[User:S8600021|Mark Hill]] 18:28, 11 August 2011 (EST) Your group left the lab today without notifying me of your selected group topic.<br />
<br />
Sorry, we were the group that hadn't quite made up their mind yet, as you said we should have a think but decide within the next few days, we thought we didn't have to make a decision on the spot. Sorry, we will make our choice soon.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
<br />
Hi guys!<br />
I agree with Elina we should just contact each other via this discussion page.<br />
I have checked out some topics and I think Duchenne Muscular Dystrophy and Angelman's syndrome look very interesting.<br />
They have many components associated like cognitive and skeletal disabilities.. <br />
Anyway let me know what you think or if you guys have looked into any topics yourselves.<br />
I also think we should meet next week if we all have a break in between the lecture and lab would you guys like to meet then?<br />
--z3294943 11:47, 6 August 2011 (EST)<br />
<br />
Sorry I couldn't write at the bottom of page I'm on my iPhone. I think we need to choose some with both anatomical changes as well as neurological and I think duchenne MD and angelman's fit those categories. They are also both genetic so let's look into both as another group maybe interested in either topic. So let's come to the lab with the two journal article required and have our first choice ready and decide during the break. How does that sound? <br />
<br />
--Karmen Magi 07:32, 8 August 2011 (EST)<br />
<br />
<br />
(Shifted Elina's contribution to discussion page. --[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST))<br />
Hey all,<br />
<br />
I had a look at the list and thought I'd start making some suggestions. I am a neuroscience student, so my interest lies in anomalies that are related to the nervous system, but I won't insist on doing something about that if noone else wants to!<br />
<br />
Here are the ones that so far seem most appealing to me:<br />
* Holoprosencephaly: the forebrain of the developing embryo fails to fold into two hemispheres. Caused by Hox genes failing to activate along the midline of the developing brain. (I've done uni stuff on Hox genes before, so I know where to start looking for material.)<br />
* Angelman's Syndrome: neurogenetic disorder with a variety of clinical features. characterised by a loss of a region of chromosome 15. this loss can be the result of varying genetic problems, including gender-related epigenetic imprinting, which makes me think that the genetics behind this Syndrome are very interesting (but I totally understand if that's just me).<br />
* Fragile X syndrome: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/ again, I find the genetics behind this very interesting.<br />
<br />
Then here's a list of the ones I [[wouldn't]] recommend doing:<br />
* DiGeorge's Syndrome, Farber's Disease, Anencephaly, as there seems to be very little known about that (correct me if I'm wrong!)<br />
* Turner's & Klinefelter Syndromes, Cystic Fibrosis - I'm just not particularly interested in them/sick of them (sorry)<br />
<br />
And here are some I had a look at and feel neutral about:<br />
* Williams Syndrome, Duchenne Muscular Dystrophy, Osteogenesis Imperfecta, Friedreich's Ataxia, Lesch-Nyhan Syndrome.<br />
<br />
As you see, I didn't go through the whole list.<br />
<br />
Let me know what you think :)<br />
<br />
<br />
--[[User:Z3389343|Elina Jacobs]] 18:43, 7 August 2011 (EST)<br />
<br />
Hi guys,<br />
<br />
Duchenne Muscular Dystrophy sounds quite interesting to me - the anatomical changes (musculoskeletal) would be something i'm more comfortable in as i haven't done any physl, neuro or genetics course. as i'm an anatomy major i think i can contribute more with physical changes - as for molecular problems i'm not very strong with that.<br />
Meeting up before the practical on Thursday sounds like a good time to meet up.<br />
--[[User:Z3329495|Z3329495]] 22:45, 7 August 2011 (EST)<br />
<br />
<br />
Hey All<br />
<br />
looks like I'm last to contribute though, even so i did some searching for journals and reasearch papers and there is a fair bit on Duchenne Muscular Dystrophy though i am sorry i wasn't able to find a abnormality myself as it was my Mums birthday on the weekend so was busy planning that so i will find one by the next lab. Also im free the gap before the lab so if we are meeting after the lecture then I'm available.<br />
<br />
--z3332250 22:29, 8 August 2011 (EST)<br />
<br />
----<br />
Articles<br />
*Review article [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/11834588 PMID:11834588]<br />
*Research article[http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20139167 PMID:20139167]<br />
--z3294943 19:28, 8 August 2011 (EST)<br />
<br />
<br />
There are at least two other groups that are looking at Duchenne Muscular Dystrophy, so I think it's good if we keep Angelman's Syndrome as our consideration as well. I think that still has enough anatomical features to it, and as I've done some molecular biology & genetics, I'd be happy to be the one focusing on that aspect. I'll try and find research and review articles on that today, so we can compare on thursday!<br />
--[[User:Z3389343|z3389343]] 11:15, 9 August 2011 (EST)<br />
<br />
Sure thing, so we're looking up articles on angelman's syndrome then?<br />
<br />
Review article: http://jmg.bmj.com/content/40/2/87.short<br />
Research article: http://jmg.bmj.com/content/38/12/834.abstract<br />
<br />
--[[User:Z3329495|Z3329495]] 11:45, 9 August 2011 (EST)<br />
<br />
'''Peer Review'''<br />
<br />
* good wikipage<br />
* was able to understand it<br />
<br />
--[[User:Z3060621|z3060621]] 21:48, 28 September 2011 (EST)<br />
<br />
----<br />
<br />
Hi,<br />
<br />
I choose to do a congenial abnormality more related to anatomy abnormality of the cleft and cleft pallets.<br />
<br />
Articles:<br />
* Review Article [http://www.ncbi.nlm.nih.gov/pubmed/21358192 PMID: 21358192]<br />
*Research Article [http://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124302/?tool=pubmed PMCID: PMC3124302]<br />
<br />
--Ryan Tran 12:39, 9 August 2011 (EST)<br />
----<br />
<br />
Here are two more about Angelman Syndrome:<br />
<br />
* Review: http://www.ncbi.nlm.nih.gov/pubmed/15668046<br />
* Research: http://www.ncbi.nlm.nih.gov/pubmed/8958335<br />
<br />
--[[User:Z3389343|z3389343]] 21:09, 9 August 2011 (EST)<br />
----<br />
hey, the second link seems to be broken?<br />
--Z3329495 22:25, 10 August 2011 (EST)<br />
<br />
----<br />
Hi everyone,<br />
I think we need to choose exactly what we are doing for the assessment before the week end.<br />
I checked out holoprosenchephaly i think it is really neuro based and from what i have read ryan and i would like to do something more anatomical..<br />
maybe we could try and decide on something that has all the components we are interested in and by the end of the weekend have made a decision.<br />
<br />
I thought maybe Friedreich Ataxia kind of embodies all aspects we are interested in..<br />
It is a defect of the nervous system which lead to muscular problems, special sensory organ problems, diabetes, heart problems and the genetics are well understood..<br />
from what i see there is quite a lot of info on it..<br />
so can we please come to a decision soon.. I think it will be easy to section think disease up eg history, embryonic development, the abnormality and when/where.how it occurs, the genetic component, neurological problems, skeletal muscle degeneration, structural/anatomical problems in the heart optic and auditory, diagnosis, treatment and what may happen in the future.<br />
let me know what you think or if you have any other disease with similar categories so everyone in the group is happy with our choice.<br />
--z3294943 17:37, 11 August 2011 (EST)<br />
<br />
Jup I'm happy with that, as I've kinda mentioned already above, it's one of the topics that I'm not fuzzed about either way. If the others agree, I'm happy to go ahead. And thinking about it, it will probably be easier than deciding on a particular case of holoprosencephaly that will make everyone happy.<br />
--[[User:Z3389343|z3389343]] 18:40, 11 August 2011 (EST)<br />
<br />
Hey everyone this link from omim might give us better understanding of Friedreich Ataxia..[http://omim.org/entry/229300?search=Friedreich%20Ataxia&highlight=ataxia%20friedreich%20ataxias%20friedreichs]<br />
If you guys have any other suggestions please let me know soon. As I would like to get start on categorising the aspects of the disease we choose and dividing them among the group.. have a good weekend! z3294943<br />
<br />
----<br />
<br />
read the link provided - looks good to me! seems pretty interesting in that you only get onset in late childhood to early teens. I'll be happy to do Friedreich ataxia.<br />
--z3329495 22:20, 13 August 2011 (EST)<br />
<br />
Ok great so have we decided on Friereich Ataxia?? DId you all want to meet in the computer room before the next lab in the break we have on thursday. Sorry i missed it last time but i thought we were meeting in the comp room and by the time i went to the lec room you were all gone :( I think we should discuss the aspects we want to research maybe we could all come with a few ideas that we each find interesting for thursday? What do you guys think? --Karmen Magi 11:09, 14 August 2011 (EST)<br />
<br />
<br />
I came across Rubinstein-Taybi syndrome and thought that seemed quite interesting so I thought I'd suggest it: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002229/. Though if we're all happy with Friedreich's Ataxia let's go ahead with that. Aren't we missing somebody's opinion still?<br />
--[[User:Z3389343|z3389343]] 15:02, 14 August 2011 (EST)<br />
<br />
<br />
----<br />
[[File:Oxidative Stress Response in Friedreich Ataxia.jpg|thumb|Oxidative Stress Response in Friedreich Ataxia]]<br />
--Karmen Magi 11:43, 14 August 2011 (EST)<br />
<br />
---<br />
<br />
i think that's everyone? So we're settled on Friedreich's Ataxia?<br />
--[[User:Z3329495|z3329495]] 10:17, 15 August 2011 (EST)<br />
----<br />
<br />
[[File:Gene expression responses of Friedreich's ataxia.jpg|thumb|Gene expression responses of Friedreich's ataxia]]<br />
<br />
<br />
Im ok with with Friedreich Ataxia it looks interesting I got nothing wrong with it.<br />
<br />
<br />
--z3332250 23:48, 15 August 2011 (EST)<br />
<br />
[[File:Pathogenesis of Friedreich Ataxia.jpg|thumb|Pathogenesis of Friedreich Ataxia]]<br />
<br />
--[[User:Z3329495|Amanda Tan]] 11:30, 16 August 2011 (EST)<br />
<br />
----<br />
Ok great so i think we have finally decided! Are we still ok to meet between the lecture and lab this thursday? I think we should started working out what aspects of the disease we are interested in and what should be included on the wed page.. <br />
Could we all come with some ideas like pathogensis etc<br />
let me know if you guys want to meet.. if so i think the computer room would be best. --Karmen Magi 20:20, 16 August 2011 (EST)<br />
<br />
<br />
Yes that sounds good to me. And meeting in the computer room is fine, provided it is free, which I assume as it seemed to be last week? --[[User:Z3389343|z3389343]] 22:10, 16 August 2011 (EST)<br />
<br />
----<br />
<br />
[[File:Frataxin mRNA levels and histone modifications on chromatin in the first intron of the frataxin gene in KIKI and WT mice.png|thumb|Frataxin mRNA levels and histone modifications in KIKI and WT mice]]<br />
<br />
<br />
<br />
Suggested Outline:<br />
<br />
#Background: <br />
##History<br />
##Epidemiology<br />
#Genetics: <br />
##Inheritance<br />
##genetic expression (pre- and postnatally)<br />
#Pathogenesis: <br />
##first genetics aspect<br />
##lead into physiology<br />
#Pathophysiology & Clinical Symptoms - link them together<br />
#Clinical aspect - split it into symptoms and complications<br />
#Diagnosis (in table)<br />
#Treatment (include genetic sreening)<br />
#Current Research<br />
#Glossary<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
<br />
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<br />
Karmen, i think this might be of interest to you. It includes historical information on Friedreich's ataxia: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062632/?tool=pmcentrez Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics]<br />
<br />
Elina, this might be of use to you? [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373517/?tool=pmcentrez HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model] I tried reading through it but too much vital information about genetics just went right over my head. It looks promising in terms of research into treatment. Also: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859089/?tool=pmcentrez The Structure and Function of Frataxin] Possibly useful in genetics component when describing frataxin?<br />
<br />
Novel treatment: [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/?tool=pmcentrez Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia]<br />
<br />
--Z3329495 19:31, 19 August 2011 (EST)<br />
<br />
Hi all, i'm having trouble locating information on the muscular effects of Friedreich's Ataxia. I've found much more information on the cardiac aspect of Friedreich's Ataxia but if anyone has found anything even mentioning muscular effects please let me know! all the papers i've located only mentions it in one or two lines.<br />
<br />
--Z3329495 19:03, 22 August 2011 (EST)<br />
Antioxidant treatment:<br />
http://www.ncbi.nlm.nih.gov/pubmed/15824263<br />
<br />
Prenatal detection of Friedreich: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320340327/abstract<br />
<br />
Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/20339857<br />
The dorsal root ganglion in Friedreich's ataxia.<br />
http://www.ncbi.nlm.nih.gov/pubmed/19727777<br />
--z3294943 10:32, 25 August 2011 (EST)<br />
<br />
Mitochondrial impairment of human muscle in Friedreich ataxia in vivo: http://www.sciencedirect.com/science/article/pii/S0960896600001085<br />
<br />
<br />
Elina, if you could find this article it'd be a great help - A preliminary study of dynamic muscle function in hereditary ataxia.: http://www.ncbi.nlm.nih.gov/pubmed/7214252<br />
<br />
--[[User:Z3389343|z3389343]] 17:23, 25 August 2011 (EST) so I can get access to this journal via Edinburgh Uni, but for some strange reason, there is no full text..? it's really weird. sorry :/<br />
<br />
I found some things as well on Signs and a bit on heart:<br />
<br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484058/?tool=pmcentrez Chest pain during exercise as first manifestation of Friedreich's ataxia.]'''<ref><pubmed>484058</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC482403/?tool=pmcentrez Left ventricular function in Friedreich's ataxia. An echocardiographic study.]'''<ref><pubmed>482403</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277199/?tool=pmcentrez Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich's ataxia.]'''<ref><pubmed>1277199</pubmed></ref><br />
<br />
'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894724/?tool=pmcentrez Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease]'''<ref><pubmed>1894724</pubmed></ref><br />
<br />
<br />
<references/><br />
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Ryan Tran 10:55, 25 August 2011 (EST)<br />
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<br />
Carnitine therapy and muscular biopsies<br />
http://jcn.sagepub.com/content/17/6/453.full.pdf+html<br />
http://www.ncbi.nlm.nih.gov/pubmed/12174969<br />
--z3294943 10:59, 25 August 2011 (EST)<br />
<br />
Cognitive impairment in spinocerebellar degeneration. it could be interesting to talk about cognitive elements of FRDA<br />
http://www.ncbi.nlm.nih.gov/pubmed/19295212<br />
<br />
[[File:Chelator and vehicle effect on hematological indices.png|thumb|Chelator and vehicle effect on hematological indices. This is of note for using Chelator as a treatment option for FA (in particular cardiomyopathy).]]<br />
<br />
For the glossary, i think we should bold the words we've put in the glossary for easy reference. what do you guys think? i've done two words in that style so see if you think it'll be a good idea to do.<br />
--Amanda Tan 16:32, 25 August 2011 (EST)<br />
<br />
<br />
For the current research: http://www.future-science.com/doi/abs/10.4155/cli.11.93?journalCode=cli<br />
--[[User:Z3389343|z3389343]] 22:18, 25 August 2011 (EST)<br />
<br />
Also, I think there will be different genetic factors that will have influences on the severity of the syndrome, I'll mention that in my genetics bit but won't go into detail about what the actual pathophysiology is, I'll just introduce it and then somehow mention that the pathophysiology will be dealt with in subsequent sections. Does that sound alright?<br />
Here's an example: http://www.ncbi.nlm.nih.gov/pubmed/11269509<br />
Also, if you find there's a genetic component mentionned, just let me know about that article and I'll make sure I cover the genetic explanation, so you can just mention that for details on the genetics, refer to the genetics section. Do you think that makes sense?<br />
<br />
I think you could just add it into the pathophysiology part since you already read it? Right now i've just been reading all articles related to cardio and adding them into the relevant sections. Not that you should do other sections, but i think if you come across something relevant to another section it'd be easier if you just added it in rather than have the person doing that section read it all again to add it in?<br />
<br />
Hey elina this might be helpful in understanding the frataxin gene. http://www.springerlink.com.wwwproxy0.library.unsw.edu.au/content/237n26h5wj083865/<br />
-z3294943<br />
<br />
Prenatal diagnosis FRDA http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/9742572<br />
-z3294943<br />
<br />
what is the intron-1 of the frataxin gene? the paper "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia" mentions it as an important part for ventricular hypertophy in relating GAA repeats in the intron-1 of the frataxin gene.<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/21055653 Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment.] can someone please help me find this article? the UNSW database seems to have it but it won't allow me access to the full article even after opening it from Sirius.<br />
<br />
<br />
explanation of an intron:<br />
<br />
I guess you know how the coding bit of a gene is transcribed from DNA to mRNA (messenger RNA), which then gets translated into protein? basically, the preliminary RNA transcript you get is hardly ever translated into protein as such, there are a few modifications that happen first. one of these is that parts of the mRNA get cut out - this is called splicing. the bits that are cut out and not used for the translation are called introns. why exactly this mutation that sits in the intron, hence the part that is cut out, has such a big effect is quite interesting; haven't had the time to read thoroughly through the papers yet to find out why exactly that has an effect. but does this explanation help so far?<br />
so intron-1 would be the first bit that is cut out of the mRNA molecule you get from the frataxin gene.<br />
<br />
Hey guys!<br />
here are some ways of diagnosis/characterising the progression of FRDA<br />
<br />
* electromyogram (EMG), which measures the electrical activity of muscle cells,<br />
* nerve conduction studies, which measure the speed with which nerves transmit impulses,<br />
* electrocardiogram (ECG), which gives a graphic presentation of the electrical activity or beat pattern of the heart,<br />
* echocardiogram, which records the position and motion of the heart muscle,<br />
* blood tests to check for elevated glucose levels and vitamin E levels, and<br />
* magnetic resonance imaging (MRI) or computed tomography (CT) scans, tests which provide brain and spinal cord images that are useful for ruling out other neurological conditions.<br />
and i have been seeing this come up alot for treatment [http://www.ncbi.nlm.nih.gov/pubmed/21392622]<br />
<ref name="PMID 21392622"><pubmed> 21392622</pubmed></ref><br />
--z3294943 19:39, 29 August 2011 (EST)<br />
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<br />
guys, you scare me with the amount of info you've already put up, but it's looking good! I really don't want to be lagging behind but I'm really stressing out with what I need to do this week, I'll try to put some stuff up but it won't be much. I promiss I'll work intensively on it the week it's due, cause before that I just won't have much time. sorry!<br />
I do have a couple more genetics related references, they're on my own student page at the mo as I didn't wanna keep adding them randomly into the discussion, but thought it would be better to just put them here once I have a reasonable pool together that I've gone through and checked for relevance.<br />
<br />
A possible teratogen? Taurine.. http://www.ncbi.nlm.nih.gov/pubmed?term=friedreich%20ataxia/embryology&cmd=correctspelling<br />
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Hi guys just with in text referencing eg... Tsou ''et al'', (2011) <ref name="PMID21652007"><pubmed>21652007</pubmed></ref><br />
lets just do the last name of first author et al and date + ref after!<br />
<br />
Hey Ryan, could you do the table up (about the stuff carmen mentioned today) in diagnosis?<br />
<br />
Hi guys! hope your enjoying you time off! I came across this book on pubmed it has PMID [http://www.ncbi.nlm.nih.gov/pubmed/20301458] i think we all should have a look it has alot of info!! hope you find it helpful! --z3294943 11:10, 5 August 2011 (EST)<br />
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Looks great! thanks! it'll help with the treatment section! --z3329495 22:09, 5 September 2011 (EST)<br />
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<br />
I've edited the treatment section but the person who filled in information on antioxidants please go through it and rewrite some of it. I didn't know all the information so i was hesitant to edit anything. Also include a sentence or two explaining why antioxidant treatment will work.<br />
--z3329495 18:03, 8 September 2011 (EST)<br />
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Our references are missing?! i just noticed it! i fixed up some strange references, but it didn't fix it! if it doesn't reappear by next week we should talk to Mark.<br />
<br />
--z3329495 19:51, 8 September 2011 (EST)<br />
<br />
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Hi guys,<br />
Are we able to meet on the wednesday of next week?? I think we really need to go over this project.<br />
We also need to add in more picture. So please if you find anything related to your subject please add it in. I am having trouble finding any picture that i am able to reuse so im having to draw alot of mine. so even if you cant find something please add a drawing or video. <br />
just to reiterate what sections everyone is meant to be working on:<br />
<br />
*Amanda: pathpart of cardio & musculature, pathpart of pathogenesis, diagnosis<br />
*Elina: Genetics, molecular & cellular parts of neurophysio aspect, current research<br />
*Karmen: Neurophysiology aspect, background, history<br />
*Ryan: Treatment, physiopart of pathogenesis, physiopart of cardio and musculature<br />
everyone: make drawing, decide at the end which one we think is best, find video of possible<br />
<br />
Amanda are you doing diagnosis?? I think there is a few other ways that can be used like MRI/ECG. It might be interesting to add these in with pictures??<br />
What do you think?<br />
And Ryan I thought maybe we could add in some treatment option for the deformities like scoliosis? Ie surgery.. Is there anything to aid with pes cavus? <br />
Have patient been able to survive heart transplantations? as this is the main cause of death would it help if they received a transplant?<br />
I have also read some info about 5-hydroxytryptophan being used as an option of treatment. <br />
Anyway let me know what you guys think?<br />
--z3294943, 9 September, 2011 (EST)<br />
<br />
Hi, yes i'm working on the table of stuff for diagnosis - its on my student page since i'm not done with it yet i didn't want to post it on the main page. Wednesday of next week is fine for me.<br />
<br />
--z3329495 22:41, 9 September 2011 (EST)<br />
<br />
Well for treatment i could only find clinical tested treatments for mainly cardiac related, but i think its a good idea for treatment for scoliosis. One more question has anyone done a hand drawing yet?.<br />
<br />
----Ryan Tran 10:44, 10 September 2011 (EST)<br />
<br />
I've put up the scoliosis one for the drawn image. also, there is new research into a different kind of iron chelation drug called deferiprone http://www.ncbi.nlm.nih.gov/pubmed/21791473 I've used a bit of this in the diagnosis for MRI (since this paper used MRI technology) but i think it'd worthwhile to put it into the current research.<br />
--z3329495 14:18, 10 September 2011 (EST)<br />
<br />
Is Elina working on prenatal diagnosis? I've included prenatal and genetic testing in the table i'm working on but i have no information on either. I'm just about finished with the table so i'll just post it on the main page to see how it looks like and what you guys think of it.<br />
--z3329495 17:26, 10 September 2011 (EST)<br />
<br />
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<br />
What time we all meeting on Wednesday? and where?<br />
<br />
Ryan Tran 23:42, 12 September 2011 (EST)<br />
<br />
Hi guys,<br />
unfortunately I am unable to come tomorrow i have some family issues. sorry!<br />
but i think that thurs will be ok just for final lay out decisions. We need more pics.. so maybe we could all find 2/3 each i think think that would brighten up the page!!<br />
If you guys still want to meet tomorrow you can. <br />
z3294943<br />
<br />
<br />
Hi guys, yes I (Elina) am working on prenatal diagnosis - do you want me to simply do it in the same kind of table format, and not have a subsequent section about it beneath? I think the table looks good, and I'd probably just be repeating myself.<br />
--[[User:Z3389343|Elina Jacobs]] 19:14, 13 September 2011 (EST)<br />
<br />
Hey Elina, could you just post a link to that paper with the muscular info here? I can get something knocked out as soon as.<br />
--z3329495 13:26, 16 September 2011 (EST)<br />
<br />
Hi guys, I heard today that monday maybe the last day we can upload something for the peer review. So if you have anything else you would like to add please get it done before then just incase!<br />
I hope everyone has a great weekend! --Karmen Magi 20:16, 16 September 2011 (EST)<br />
<br />
Amanda, here's the reference I was telling you about: Massimo Pandolfo Friedreich ataxia. Handb Clin Neurol: 2011, 103();275-94 PMID:21827895<br />
It's a 20 pages review on what is known about FRDA so far, hopefully you'll find some useful stuff about the muscular aspect in it!<br />
<br />
Ryan: here's the genetics treatment article I was talking about: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001958<br />
let me know if you're struggling with the genetic "jargon" and I'll help you out.<br />
<br />
--[[User:Z3389343|z3389343]] 11:44, 17 September 2011 (EST)<br />
<br />
Hey Elina, there isn't anything much on the muscular system in that review but i found a paper which i cannot get access to on the UNSW database. If you could access it through your university it would help me a ton! [http://www.ncbi.nlm.nih.gov/pubmed/7634585 | Natural history of muscle weakness in Friedreich's Ataxia and its relation to loss of ambulation.]<br />
<br />
Oh no, sorry about that! Also, your link doesn't work for me :/<br />
<br />
Should work now - must be because i didn't put a space somewhere...<br />
<br />
Sorry, but I can't get access to it either...<br />
<br />
==Peer Assessments==<br />
* Epidemiology was a bit brief and perhaps could be expanded on or supported with statistics from multiple nations etc.<br />
* Aetiology section was really detailed and had a great span of information. Your image of the Friedreich’s pedigree could perhaps be slightly bigger on the page because I missed it the first time viewing your page.<br />
* The neuropathology section was extremely ‘full’. The amount of text in heavy paragraphs may be off putting to some readers. A suggestion would be to break it down with the inclusion of tables and maybe dot-pointing the information that can be summarised.<br />
* Maybe include a glossary so you can accommodate for all readers.<br />
* It was good to see that you grouped your references :) <br />
--[[User:Z3332629|z3332629]] 15:29, 22 September 2011 (EST)</div>Z3389343https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Friedreich%27s_Ataxia_Pedigree.png&diff=76632File:Friedreich's Ataxia Pedigree.png2011-10-10T06:42:47Z<p>Z3389343: The pedigree of a family affected by Friedreich's Ataxia. Due to the anticipating nature of the inheritance, the severity of symptoms increases while the age of onset decreases with each generation. Heterozygous individuals who possess one allele with the</p>
<hr />
<div>The pedigree of a family affected by Friedreich's Ataxia. Due to the anticipating nature of the inheritance, the severity of symptoms increases while the age of onset decreases with each generation. Heterozygous individuals who possess one allele with the repeat expansion do not develop symptoms, and are thus unaffected carriers. The expression of Friedreich's Ataxia occurs only when an individual carries two mutated frataxin alleles.<br />
Please note that this pedigree is entirely fictional and solely serves as a model to illustrate the mode of inheritance.<br />
<br />
'''Copyright''' Beginning six months after publication, I (z3389343) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode<br />
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