{{2011Student}}

= '''Lab Attendance''' =

--[[User:Z3290815|Z3290815]] 12:52, 28 July 2011 (EST)

--[[User:Z3290815|z3290815]] 11:05, 4 August 2011 (EST)

--[[User:Z3290815|z3290815]] 11:08, 11 August 2011 (EST)

--[[User:Z3290815|z3290815]] 11:01, 18 August 2011 (EST)

--[[User:Z3290815|z3290815]] 11:04, 25 August 2011 (EST)

--[[User:Z3290815|z3290815]] 11:03, 1 September 2011 (EST)

--[[User:Z3290815|z3290815]] 11:08, 15 September 2011 (EST)

--[[User:Z3290815|z3290815]] 12:52, 22 September 2011 (EST)

--[[User:Z3290815|z3290815]] 11:08, 29 September 2011 (EST)

--[[User:Z3290815|z3290815]] 11:04, 6 October 2011 (EST)

= '''Lab 1: Assessment''' =

== 1. Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique. ==

In Vitro Fertilization is one technique used in Assisted Reproduction Technology (ART) in which fertilization occurs outside of the body. In Vitro Fertilization is given its name from Latin origins; In Vitro meaning “in glass”. This is referring to the test tubes in which fertilization occurs, hence, the colloquial term for IVF babies are “test tube babies”. The first successful birth of an IVF baby was named Louise Brown born in the United Kingdom on the 25th of July, 1978. The development of In Vitro Fertilization and the successful birth of Louise Brown were by Robert G. Edwards. Consequently he received the Nobel Prize in Physiology or Medicine in 2010 for his developments. Although it wasn’t until 1978 when the first successful IVF human birth occurred, IVF can be dated as far back as the 1980’s by Walter Heape. He was a professor and physician and had conducted research on reproduction in multiple animal species and reported the first known case of embryo transplantation in a rabbit.

== 2. Identify a recent paper on fertilisation and describe its key findings. ==

The aim of this article<ref><pubmed>21716935</pubmed></ref> is to emphasize the advantages and the disadvantages of intracytoplasmic injection of sperm (ICSI) and how to maximise these potential benefits while minimising its complications. ICSI involves micromanipulation techniques involving the direct injection of spermatozoa into the oocyte.

'''Advantages:'''

* ICSI helps males with severe infertility which cannot be amended through medicine or surgery the option to parent a genetically related child.

* ICSI is used to alleviate severe male factor infertility due to the lack of sperm in the ejaculate due to severely impaired spermatogenesis.

* Previously the primary treatment option for infertile men with obstructive azoospermia was vasovasostomy or vasoepididymostomy to reverse vasectomy.

'''Disadvantages:'''

* There is increasing evidence of the involvement of genetic factors in male infertility and the potential risk of transmission of genetic disorders to the offspring.

* A thorough genetic evaluation of the couple, classification of infertility and adequate counselling of the implications and associated risks prior to embarking on the procedure is necessary.

== 3. Identify 2 congenital anomalies. ==

A congenital anomaly is when there is something unusual or different at birth. This can be a minor anomaly whereby the anomaly has no serious medical or cosmetic concern or a major anomaly where there is a serious medical or cosmetic concern for example:

* '''Atrial septal defect (ASD:''' form of congenital heart defect that enables blood flow between the left and right atria via the Interatrial septum.

* '''Spina bifida:''' a developmental congenital disorder and neural tube defect caused by an incomplete closing of the embryonic neural tube.

= '''Lab 2: Assessment''' =

== 1. Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation. ==

For fertilization to occur, the sperm must migrate through a layer of follicle cells and then bind to the egg coat called the zona pellucida. The crucial protein which allows the binding of a capacitated sperm to the zona pellucida is ZP3. As the binding is occurring, the sperm undergoes an acromosome reaction where exocytosis is released. This helps the sperm to maintain a tight binding to the zona pellucida while burrowing. Two mechanisms are in operation to block polyspermy from occurring (ensures that only one sperm fertilizes the egg); the primary block is the depolarization of the egg plasma membrane and the secondary block is provided by the egg cortical reaction.<ref>B. Alberts, A. Johnson, J. Lewis, et al. '''Fertilization.''' Molecular Biology of the Cell. 4th edition. http://www.ncbi.nlm.nih.gov/books/NBK26843/</ref>

== 2. Identify a review and a research article related to your group topic. ==

'''Research Articles:'''

'''Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure in Mice Carrying the Egr2 I268N Mutation'''<ref><pubmed>19244508</pubmed></ref>

* Describes the engineering and characterisation of a mouse carrying the I268N mutation in Egr2.

* The proper formation of myelin by Schwann cells requires a series of transcription factors including SOX10, SCIP/Oct6, Egr2, and Nab1/Nab2.

* A loss of these transcription factors disrupts the myelination process, as does persistent overexpression.

* This was observed in patients with recessively inherited Charcot–Marie–Tooth (CMT) disease type 4E, which is predicted to alter the ability of Egr2 to interact with the Nab transcriptional coregulatory proteins.

* Charcot–Marie–Tooth disease (CMT) is a common inherited disorder of peripheral nerves characterized by progressive sensory loss and weakness beginning in the feet and legs, and later progressing to the hands

* Mice homozygous for Egr2I268N developed a congenital hypomyelinating neuropathy similar to human counterparts.

* Egr2I268N is expressed at normal levels in developing nerve but is unable to interact with Nab proteins or to properly activate transcription of target genes critical for proper peripheral myelin development.

* Egr2I268N/I268N mutant mice maintain normal weight and have only mild tremor until 2 weeks after birth, at which point they rapidly develop worsening weakness and uniformly die within several days. Nerve electrophysiology revealed conduction block, and neuromuscular junctions showed marked

'''Congenital hypomyelinating neuropathy'''<ref><pubmed>10207934</pubmed></ref>

* Describes the symptoms of two patients with congenital hypomyelinating neuropathy

* Hypotonia = low muscle tone (amount of tension or resistance to movement in a muscle)

* Areflexia = absence of neurologic reflexes such as the knee jerk

* Distal muscle weakness

* Atrophy = wasting of a part of the body

* Exceedingly slow nerve conduction velocities

* Usually leading to early death or severe disability.

* It contains great images of the histology of the condition as well as the actual patients

* It contains a detailed recount of sural nerve biopsies of the patients

* It compares the symptoms of congenital hypomyelinating neuropathy in Trembler mice as they are very similar to human symptoms

'''Review Article:'''

'''Congenital hypomyelinating neuropathy: two patients with long-term follow-up'''<ref><pubmed>4087003</pubmed></ref>

* Review of previously reported cases of congenital hypomyelinating neuropathy (CHN) aswell as two unrelated females with CHN

* The first patient is now 9 years old and has showed continual improvement of motor function even though her follow up nerve conduction velocities remained unchanged

* The second patient is now 5 years old and has also showed continual motor function improvement since her first visit even though her follow up nerve conduction velocities also remained unchanged

----

[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg|thumb|Differentially expressed RefSeq genes in human trisomy 21]]

[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg|350px]]

File:Differentially expressed RefSeq genes in human trisomy 21

= '''Lab 3: Assessment''' =

== 1. What is the maternal dietary requirement for late neural development? ==

'''Iodine'''<ref><pubmed>21765996</pubmed></ref> is an essential maternal dietary requirement for late neural development. Foetal thyroidogenes occurs by approximately the twelfth week of gestation and the foetal thyroid is capable of organifying iodine by approximately the 20th week of gestation. Before this time, maternal T4 is the only form of thyroid hormone that can traverse the placenta in small amounts. This must be adequate to meet the metabolic needs of the foetus.

Iodine deficiency remains the leading preventable cause of mental retardation worldwide.

'''Effects of Severe Iodine Deficiency:'''
* Potential to cause both maternal and foetal hypothyroidism.
* Poor obstetric outcomes including spontaneous abortion, prematurity, breech birth and stillbirth associated with adverse effects on the foetus including congenital anomalies, decreased intelligence, and neurological cretinism (which includes spasticity, deaf mutism, mental deficiency, and squint).
* Linked to intellectual development in early childhood in the absence of overt mental retardation.
* The IQ of iodine-sufficient children, on average, was 12.45 points higher.

'''Effects of Mild-to-Moderate Iodine Deficiency:'''
* Less well understood than those of severe iodine deficiency but effects foetal neurodevelopment.
* The infants with lower maternal fT4 had significantly lower psychomotor scores.
* They found that lower maternal fT4 was associated with an increased risk of expressive language delay.
* Significantly greater prevalence of attention deficit hyperactivity disorder (ADHD).
* The IQ of iodine-sufficient children, on average, was 7 points higher.

The United States Institute of Medicine’s recommended daily allowance for iodine is 220mcg during pregnancy and 290mcg during lactation [20].

== 2. Upload a picture relating to you group project. ==

[[File:Hippocampal_Formation.jpg‎|600px]]

'''Figure 1: Hippocampal formation.'''<ref><pubmed>21303513</pubmed></ref>

Images of the hippocampal formation at the level of the lateral geniculate body from (A) patient 1 and (C) patient 3 show abnormal expansion of CA1 by increased numbers of pyramidal neurons. These are compared with the more usual hippocampal microarchitecture that shows a thinner linear band of neurons in CA1, as seen in (B) a 62-year-old male control. Haematoxylin and eosin, original magnification ×10; scale bar = 1 mm. Arrow indicates bulge/expansion composed of increased numbers of pyramidal cells in (A) patient 1 and (C) patient 3.

'''Copyright:''' This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

File: Hippocampal_Formation

= '''Lab 4: Assessment''' =

== 1. The allantois, identified in the placental cord, is continuous with what anatomical structure? ==

The allantois is an endodermal evagination of the developing hindgut which collects liquid waste and exchange gases used by the embryo. Therefore the allantois is connected to the fetal bladder via the urachus.

== 2. Identify the 3 vascular shunts, and their location, in the embryonic circulation. ==

* '''Ductus arteriosus:''' is a shunt connecting the pulmonary artery to the aortic arch which allows most of the blood from the right ventricle to bypass the foetus's fluid-filled lungs.

* '''Ductus venosus:''' shunts the blood flow of the umbilical vein directly to the inferior vena cava. To allow oxygenated blood from the placenta to bypass the liver.

* '''Foramen ovale:''' allows highly oxygenated blood to communicate between the left and right atrium.

== 3. Identify the Group project sub-section that you will be researching. ==

* History
* Epidemiology

= '''Lab 5: Assessment''' =

== 1. Which side (L/R) is most common for diaphragmatic hernia and why? ==

90% of foetal diaphragmatic hernias are found on the left side of the diaphragm. Depending on how large the hole is, the intestines, spleen, liver and/or stomach may move up into the chest cavity causing the lungs to develop poorly.

= '''Lab 6: Assessment''' =

== 1. What week of development do the palatal shelves fuse? ==

The primary palate fuses in the human embryo between week 6 and 7. The secondary palate fuses in week 9 of embryological development which requires the growth of the palatal shelves.

== 2. What early animal model helped elucidate the neural crest origin and migration of neural crest cells? ==

Both the chicken model and quail-chick chimeras were used as early animal models which helped explain the neural crest origin and migration of neural crest cells. Chicken embryo sequencing can show the migration of Dii-labelled neural crest cells towards the brachial arches and Nicole Le Douarin pioneered the quail-chick in the 1980’s as a way to study the migration path and final destination of transplanted neural crest cells.

== 3. What abnormality results from neural crest not migrating into the cardiac outflow tract? ==

If neural crests do not migrate to the cardiac outflow tract, than due to the reduction in number of cells added to the myocardium of the distal outflow tract, there will be a subsequent shortening of this tract. The shortened outflow tract leads to an altered cardiac looping. This malalignment of the outflow tract is seen as a dextroposed aorta which in babies, is classified as the congenital abnormality Tetralogy of Fallot<ref>http://circ.ahajournals.org/content/106/4/504.full.pdf</ref>.

= '''Lab 7: Assessment''' =

== 1. Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy? ==
A study using ablation techniques on the gastrocnemius muscle of mice showed that even with the exposure to tamoxifen or the loss of satellite cells, the muscle did not alter the cell population. It also showed the same two-fold increase in the plantaris muscle weight. This suggests that satellite cells are not necessary for muscle hypertrophy. Satellite cells are however, involved in the regeneration of muscle growth with results suggesting that the muscle growth of the mice in the ablation group were significantly blunted in muscle depleted of satellite cells<ref><pubmed>21828094</pubmed></ref>.

== 2. Why does chronic low frequency stimulation cause a fast to slow fibre type shift? ==
Muscle fibre type is controlled by several factors such as;
* Impulse activity,
* Neurotrophic factors
* Spinal motoneurons
* Myogenic factors
* Physiological
* Demand of the muscle
* Hormones<ref><pubmed>1295870</pubmed></ref>
Therefore by inducing Chronic Low frequency stimulation (CLFS) of the nerves innervating fast twitch muscles, it induces satellite cell content and activity causing phenotypic changes causing the fibres to shift in type<ref><pubmed>16439424</pubmed></ref>.

== 3. Trisomy 21 Peer Review ==

'''Introduction:''' The image here is lacking an appropriate title and is not properly cited. The text should give a brief overview of Trisomy 21 without overwhelming the audience with statistics. The definitions of “Down Syndrome” and “aneuploidy” would fit better under the glossary heading or made to fit into the text so that it does not disrupt the flow of reading.

'''Some recent findings:''' This subheading would be better suited towards the end of the page to allow the reader to obtain a good understanding of what Trisomy 21 actually is before jumping into recent findings. The content here though is very thorough and easy to read due to the bolded headings and the use of an image here is a great way to break up a big chunk of text.

'''Associated congenital abnormalities:''' This section could benefit by increasing the image size and including a title.

'''Heart defects and Limb defects:''' These sections could be merged under one subheading such as “defects” to continue the flow of reading.

Overall the content is there, just some rearranging of text and a punchier introduction will improve this page. The ratio of text to images is especially impressive but make sure that each image relates to its section and has proper titles and citing.

= '''Lab 8: Assessment''' =

== Peer Review ==

'''Group 1:'''
* The introduction is very thorough, however the use of too many statistics and scientific terms like “partial x monosomy” make it difficult to read, especially for an introduction. By hyper-linking the glossary terms or by using a simple explanation of the word in the sentence could help make this section more reader friendly.
* The introduction also needs to be re-read to fix little mistakes such as those in the following sentences “The affected organ systems and tissues may are effected to a lesser or greater extent amongst that are affected by turner syndrome.” and “However, there still further research to be completed.” An image added to this section also wouldn’t hurt.
* I would suggest that you play around with the placement of the images in the epidemiology section. Where they are placed now disrupts the flow of the text or leaves a large blank space between the next heading, which is also disruptive. The first image can be made a little larger and the second image does not have the correct copyright or title format.
* The epidemiology section also needs to be proof read to fix little mistakes.
* The etiology section is done very well, it is very easy to read and made easier with the hyper-links to the glossary.
* Image 1 under etiology is missing <nowiki>“{{Template:2011 Student Image}}”</nowiki> and image 2 has a little mistake in the explanation “Complete absence of on effected of the X sex chromosomes...” and needs to be moved slightly so that it doesn’t indent the next heading.
* Nice referencing in the clinical manifestation section although the symptoms need to be explained more. What is it? What are the implications of it? A picture could be useful where text can’t explain a symptom.
* Diagnostic procedures section is done very well. Good balance between images, text and tables however all the images need to include<nowiki>“{{Template:2011 Student Image}}”</nowiki>. Very good student drawn images and explained very well – I didn’t even realise they were student drawn until I read that they were! Hyper-linking to the glossary is also a bonus.
*Treatment is done well especially by breaking up the text into sub-headings, some spelling mistakes though such as “Also if convex gorwth of toenails”.
*Research is very informative but by bolding the reference, it makes it hard to follow and read. Maybe if you include a space in between the findings of the paper or a table could help this section.
*The reference section needs to be fixed as references should not be listed more than once under the reference section. Read the section on “multiple referencing” under “editing basics”.

'''Group 2:'''
* The introduction is very easy to read and is accompanied by a great image, although this image should include a legend. It would be beneficial to link the image with the symptoms mentioned in the intro and to only mention a couple of important symptoms instead of listing them all here and having to repeat yourself later on.
* Very extensive historical background. Very impressive and well referenced. Image needs to include a legend.
* Epidemiology needs to be proof read as there are a couple of little mistakes that lessen the value of what is a really well researched section; “Due to the fact that 22q11.2 deletions can also resulting in signs that...”, “It has been well documented that there individuals who...” and “which may be resultant form a learning dysfunction or heart disease.”
* Etiology is also done well and is very comprehensive, however there is a spelling mistake “interstital deletions of chromosome 22” so make sure you re-read this section too.
*An image either in epidemiology or etiology would help break up a huge chunk of text.
* Pathogenesis/Pathophysiology section is very strong with great student drawn images relevant to the text. Only suggestion is to hyperlink glossary terms since there are a lot of terms in this section which need to be explained further.
* Diagnostic Test section is done well with a well formatted table making it easy to read. Some images are missing as I’m sure you’re aware of and make sure to include <nowiki>“{{Template:2011 Student Image}}”</nowiki> for these images.
* Clinical manifestations; perhaps the table describing the symptoms could immediately proceed after “The most common signs and symptoms include:” instead of having the symptoms in dot points and repeated twice. The student drawn image may benefit from pointing out that A is at rest and B is during normal speech – just to clarify. I also noticed a spelling mistake “In more severs cases..” so just make sure you go over this section with a fine comb.
* Treatment also had a couple of little mistakes for example “and consult various specialists, from example a cardiologist”. A legend for the images here would improve this section.
*Current and future research is very extensive and well researched.
Hats off to you guys!

'''Group 3:'''
* The introduction is very lengthy, some parts feel as though they would be more appropriate in other sections. The image here fits nicely with the text but it could benefit from a more descriptive legend and needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* In the history, you begin to use the short hand “KS” without an initially stating that this is the abbreviation for “Klinefelters syndrome (KS)”. The dates that are mentioned are very detailed although it ends in 1970, were there any other breakthroughs since then? A picture of Klinefelter would be a nice touch here.
* Epidemiology requires some proof reading as there are a couple of little mistakes and the images would have more of an impact if they were slightly larger.
* I like how you have linked figure 1 to the non-disjunction sub-heading under aetiology. The image in this section could benefit from a coloured legend, ie. Instead of saying “Blue circles are male cells”, in a box include an actual blue circle = male cells along with the other descriptions. It also needs to be properly cited.
* There is too much repetition between pathogenesis and aetiology, maybe discussion between these two students is needed to minimise repetition. Good hand drawn images but you need to include the student template as mentioned previously.
* Signs and symptoms would look better in a coloured table and with more images. I don’t think it is necessary to repeat the image comparing age and intellect here.
* Diagnosis; nice use of another form of media – a video. The abbreviation of KS in this section needs to be established first by placing KS after the first time you mention Klinefelters syndrome.
* Management is very concise and thorough
* Other similar defects; nice touch, it could look more appealing with the use of colour and larger images though.
* Current research is formatted nicely and flows well

'''Group 4: '''
* The introduction provides a great overview but remember it needs to be easy to read, even for those who have never heard of Huntington’s disease. If you explain scientific and medical terms (such as neurodegenerative and CAG trinucleotide tract) more generally/broadly, it will solve this problem.
* History: great use of a quote and image. The timeline would look better and make it easier to read if the dates were bolded or if it were in a table. The explanations could be elaborated more such as “1900: Mendel’s work was rediscovered”. Image needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* Epidemiology: Although you’ve stated that Venezuela and North Ireland have notably high prevalence of this disease, you haven’t stated the actual prevalence of Venezuela. You also need to re-read this section as there are a couple of mistakes eg “There seem to be an increased prevalence of Huntington's disease...” and this sentence doesn’t make sense “Two of the most well-known populations in which high prevalence of HD was notably in the state of Zulia, Venezuela and Northern Ireland”. What are HTTP haplotypes?, overall I found the explanation of the paper by Warby et al hard to understand, maybe another attempt of explaining this paper is needed by spelling out the haplotypes even more so. In saying this, the tables are formatted very nicely.
* Genetics: Nice student drawn images but just make sure you include the student template as mentioned above. The “Huntingtin Gene” section would benefit from an image of the specific regions on the chromosome as it is hard to follow with just text.
* Molecular mechanisms and pathogenesis: a lot to take on but is made easier to read through the use of good sub-headings and highlighted words and large image. Make sure you include the student template here as well and there is an image missing in this section though.
* Clinical manifestations: You have mentioned 3 classes of symptoms but have only gone into detail about one of them; motor movement impairment. What happened to cognitive and behavioural explanations? Nice student drawn image, I like how it is oriented to the left to change it up a bit.
* Diagnostic test: The table could be formatted with more colour to make it more aesthetically pleasing. I personally don’t understand including an image of another disease, i would stick to images specifically relating to HD.
* Under neuropathogy there is a little typo “The neuropathological hallmark of Huntington’s disease is now know to be the gradual loss of spiny GABAergic...”, there could be more so i would advise to check this section again.
*Under genetic testing there is also another little typo “However it wasn’t until the 1993 when...”
*Treatment and future research: very well researched and I really liked the use of the table and images here, it provides great balance and flow.

'''Group 6:'''
* Introduction: Maybe briefly explain the symptoms and the physiological implications of a tet spell and what palliative care is, alternatively hyperlink these words to the signs and symptoms and treatment sections. There are also a few mistakes such as no space after commas “chromosomes 5,20 and 25.” and an incorrect capital letter after a comma “TOF patients include, Infants turning blue”, just make sure to correct these little mistakes by re-reading this section. An image here would also be good.
*History: The history you do have is very comprehensive and easy to read, however the dates get lost in amongst the text. If you bold the dates or include a brief table after the text it will help the reader to track the history better.
*Epidemiology: Very short, could you maybe elaborate to why TOF affects slightly more males than females?
* Signs and symptoms; the information here is very good, it could be improved with the use of more images. I’m not sure if it’s just me or not but I couldn’t hear anything in the normal heart video but the TOF heart video was fine?
* Genetics: This section genuinely scared me, it is a lot of text and a lot of scientific text at that. I found it difficult to read and ended up skipping over this section. Maybe try explaining the genes in your own words. The images do help though so maybe make them bigger. I did find a little typo “gene taht results to TOF” so make sure you proof read once you’ve edited again.
* Pathophysiology and abnormalities is done really well with great visual aids (second image needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>). Only suggestion is to leave the sub-headings just bold - no need for italics.
* Diagnosis is obviously unfinished but once the images have been added, the blank text has been filled and some colour is added to the table, I think it will be a great section.
* Treatment and management: The image here is also missing the student template. Spelling mistakes found so proof reading is required “oxygen & intravenous morphine to provides more blood flow”. The table here could be coloured to liven up the page.
* Prognosis is done well but maybe a pie graph could be inserted to show the major causes of death in surgically untreated patients as a visual.
* Future directions is also very good – the referencing just needs to be fixed.

'''Group 7:'''
* Introduction may be a little short but I think it’s to the point. It does need some sort of a visual though, especially because the next two sections are also lacking images.
* History is very interesting. I like how you have incorporated a table to summarize the text. A portrait of Harry Angelman or the oil painting of “a Boy with a Puppet” would fit nicely here.
* Epidemiology needs more content.
* Etiology also needs more content or at least elaboration on what content is already there. I believe that the 4 major genetic mechanisms aren’t explained well at all. The student drawn image is really good though.
* Pathogenesis section is very good, although it is a lot to take on board it has been complimented very well by the addition of very clear student drawn images. The placement of the images needs to be reconsidered, especially since it disrupts the signs and symptoms heading.
* Signs and symptoms; the table lets this section down, I don’t quite understand the headings of the table and where the content in the table ends because it merges with the reference. Maybe use dot points or add a second colour, add outlines and bold the headings? The rest of this section is done really well with very interesting text balanced well with the images. Just make sure to re-read this section as there was a spelling mistake noticed in the last line “Whit age, patients gain...”
* Complication: if there aren’t any other complications I would suggest maybe moving this section to fit under signs and symptoms? It is interesting and worth keeping but it’s too short to be on its own.
* Diagnosis: the formatting of this section needs tweaking to make it easier to read. I understand that the first image relates to prenatal diagnosis but the terms within the flow chart aren’t explained yet so it’s hard to follow. If you align this image to the left of the text and include a title for the image “Flow chart summarizing prenatal diagnosis of Angelman’s Syndrome” than this could solve this. This image also needs a proper citation. The second image is broken and the third would be better placed on the left as well.
* Related diseases is too short, either add to it or merge it into another section (it could fit under prognosis if you create the right segue-way).
* Treatment and management is fine, maybe bold the headings of the table.
* Prognosis is ok, maybe a little short.
* Genetic counselling is again too short and doesn’t really make sense. You need to explain the table first and connect it to genetic counselling. You shouldn’t repeat information either.
* Current and future research is fine.

'''Group 8:'''
* 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.
* 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.
* 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 same cases, this...”?, “As already mentionned,” and “...investigated in mouse embroys,” so make sure that this section is proof read. Overall this section is very good and extensive.
* Pathogenesis is done well, great image to balance out text.
* 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!
* Clinical presentation: Good balance between images (could be a little larger), text and tables – it really maintains the reader’s attention.
* 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.
* Treatment: Very good
*Current research: A few key points and sentences from each paper would be nice to make this section feel more complete.

'''Group 9:'''

'''Group 10:'''

'''Group 11:'''

= '''Lab 9: Assessment''' =

N/A

= '''Lab 10: Assessment''' =

== 1. Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss. ==
== 2. Identify 3 factors that contribute to poor neonatal drainage of the middle ear. ==
== 3. Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students) ==

= '''Lab 11: Assessment''' =
= '''Lab 12: Assessment''' =
= References =
<references/>

2011 Group Project 5

2011-10-12T04:09:08Z

Z3290815: /* Glossary */

{{2011ProjectsMH}}

{{2011Projects}}

= Fragile X Syndrome =

== Introduction ==

[[File:Fragile X Chromosome..jpg|thumb|280px|'''Figure 1:''' Comparison between a normal X chromosome and a Fragile X chromosome]]

Fragile-X syndrome (FXS) is a [[#Glossary | '''congenital disorder''']] resulting from an abnormality on the X-chromosome. FXS is named for the fragile site on the X chromosome found in those affected with this syndrome. The fragile site is known as FRAXA ('''Fra'''gile site on the '''X''' chromosome site '''A''') which appears as a gap, constriction or break in [[#Glossary | '''metaphase''']] chromosomes as shown in figure 1<ref name="PMID19465392"><pubmed>19465392</pubmed></ref>. Specifically it is caused by [[#Glossary | '''methylation''']] of the CGG triplet resulting in its amplification. The expansion of the [[#Glossary | '''nucleotide triplet''']] (CGG) causes the extremity of the long arm of chromosome X to appear elongated,<ref name="PMID19718005"><pubmed>19718005</pubmed></ref> creating a site of constriction which becomes fragile and is prone to breaking<ref name="PMID6348096"><pubmed>6348096</pubmed></ref>. The amplification of this codon also results in the [[#Glossary | '''silencing''']] of the FMR1 gene.

This genetic anomaly manifests itself as a number of [[#Glossary | '''phenotypic abnormalities''']] including; physical appearance (long narrow face, prominent ears, a prominent jaw, and macroorchidism), social deficits, intellectual retardation (Low IQ, decreased working memory), speech deficits and often extreme, child-like emotions.
FXS has a strong correlation with Autism, with approximately 25-30% of FXS afflicted males meeting the diagnostic criteria for Autism.

As a genetic disorder, direct treatment of the cause is unavailable. As such, the majority of treatments target the individual symptoms associated with the disorder. These include drug treatments for Attention Deficit Hyperactivity Disorder (ADHD), aggression and seizures, as well as non-drug treatments such as counseling, environmental changes and behavioural interventions.

== History of the disease ==

{|style="width:80%; height:100px" align="center"
|-bgcolor="lightpink"
| '''Year'''
| '''Discovery'''
|-

| valign="top" bgcolor="mistyrose"|'''1910'''
| valign="top" bgcolor="lavenderblush"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of a fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="mistyrose"|'''1943'''
| valign="top" bgcolor="lavenderblush"|Martin and Bell first reported that the excess number of retarded males in the population was due to a sex linked inheritance. The two also noted that there was a lack of unusual physical features related to the mental retardation, including the shape of the head and face. Therefore Martin and Bell were also the first to report sex linked mental retardation without [[#Glossary | '''microcephaly''']] or [[#Glossary | '''microphthalmia''']]<ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="mistyrose"|'''1969'''
| valign="top" bgcolor="lavenderblush"|Herbert Lubs first documented and reported the existence of the marker X chromosome.<ref name="PMID6348096 "/>. Lubs developed the chromosomal test for Fragile X, however it was not used extensively until the late 1970's<ref name="PMID7541938"><pubmed>7541938</pubmed></ref>.
|-
| valign="top" bgcolor="mistyrose"|'''1977'''
| valign="top" bgcolor="lavenderblush"|Sutherland showed Herbert Lubs' findings to be accurate and reliable. This was done through cells cultured in a folate deficient medium<ref name="PMID7541938"/>.

Herbert and Lubs found that [[#Glossary | '''cytogenetically''']], fragile X syndrome is characterized by the presence of a folate-sensitive fragile site at Xq27.3 (FRAXA) in the lymphocytes of affected individuals<ref name="PMID7541938"/>.
|-
| valign="top" bgcolor="mistyrose"|'''1980'''
| valign="top" bgcolor="lavenderblush"|Turner and colleagues recognized the combination of [[#Glossary | '''macroorchidism''']] and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref name="PMID7541938"/>.
|-
| valign="top" bgcolor="mistyrose"|'''1991'''
| valign="top" bgcolor="lavenderblush"|Verkerk discovered and described the FMR1 gene and encouraged the medical and [[#Glossary | '''psychopedagogic''']] research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="mistyrose"|'''1992'''
| valign="top" bgcolor="lavenderblush"|Sutherland and baker discovered two other rare folate-sensitive fragile sites distal to FRAXA at Xq28, these include; FRAXE and FRAXF. Both of these fragile sites are also caused by the expansion and subsequent [[#Glossary | '''methylation''']] of the CGG [[#Glossary | '''nucleotide triplet''']], however, they have not been associated with any phenotype<ref name="PMID7541938"/>.
|-
| valign="top" bgcolor="mistyrose"|'''2001'''
| valign="top" bgcolor="lavenderblush"|Hagerman and colleagues first recognized Fragile X-associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS)<ref name="PMID11445641"><pubmed>11445641</pubmed></ref>. FXTAS is a disorder that is under-recognized because the first published report was only in 2001 and the presentation of the disorder is variable and mainly consists of a combination of signs common in the elderly<ref name="PMID19574929"><pubmed>19574929</pubmed></ref>. The core clinical symptoms of FXTAS are prominent tremors, [[#Glossary | '''ataxia''']] and cognitive decline. Cognitive decline occurs in at least 50% of the patients with neurological symptoms usually at a later age (>70 years)<ref name="PMID21476992"><pubmed>21476992</pubmed></ref>.
|-
| valign="top" bgcolor="mistyrose"|'''2010'''
| valign="top" bgcolor="lavenderblush"|Paul and colleagues deduced that the elevated [[#Glossary | '''mRNA''']] in FXS premutation carriers are vulnerable to [[#Glossary | ''' neurotoxin''']], leading to early cell death and brain disease, consistent with FXTAS symptoms<ref name="PMID7541938"/>.
|}

== Epidemiology ==

Recent data suggests that Fragile X Syndrome (FXS) approximately affects 1 in 2,500 individuals of which there is approximately equal prevalence in males and females<ref name="PMID21748281"><pubmed>21748281</pubmed></ref>.

The incidence of the premutation carriers is significantly higher with approximations of up to 1 in 251 males and 1 in 100 females noted as carriers<ref name="PMID21748281 "/>. Since FXS is an X-linked neurodevelopmental disorder, females are less likely to show severe signs of physical, cognitive and behavioural phenotypes of Fragile X due to the presence of one normal [[#Glossary | '''allele''']] <ref name="PMID21748281 "/>.

There are an inadequate number of studies conducted on FXS in other populations. However, those studies that have been done, suggests that there is a difference in prevalence across populations<ref name="PMID11545690"><pubmed>11545690</pubmed></ref>. For example:
* One study proposed that the prevalence of FXS is higher amongst Tunisian Jews compared with Caucasians by as much as 10 times more<ref name="PMID11545690"/>.
* Another study established a lack of large CGG repeats in Native American populations to suggest a lower prevalence of the syndrome amongst this population<ref name="PMID11545690"/>.
* Similarly, the Spanish Basque population has reported a lower prevalence of males with the FXS of pure Basque origin in a mentally retarded population and a lower frequency of large CGG repeats<ref name="PMID11545690"/>.
* Studies carried out on Indian Fragile X patients have shown a frequency of 7% among the mentally retarded population<ref name="PMID20090132"><pubmed>20090132</pubmed></ref>.

[[File:Fragile x inheritance.jpg|centre|400px|Fragile X inheritance for Non-symptomatic parents]]

'''Genetic Counseling'''

Genetic counseling is advised for individuals with FXS in their family history. The genetic counselor will identify individuals that are at risk for carrying FMR1 mutations by reviewing the individual’s inheritance pattern for FXS. The counselor will also assess the chances of having offspring affected by FXS and review reproductive options for future pregnancies. <ref name="PMID19117905 "/>

== Etiology ==

[[File:FMRP expression in control and fragile X tissues.png|thumb|210px|FMRP expression in control and fragile X tissues]]

Involving [[#Glossary | '''methylation''']]-induced silencing of the FMR1 gene on the X chromosome, Fragile X Syndrome is an entirely genetic disease. The disease is not necessarily hereditary; given the location of the gene on a particularly fragile segment of Xq27.3, the disease commonly occurs in people without a family history. Nonetheless, the disease is X-linked and thus likely to be passed down between generations.

At times Fragile X Syndrome may occur due to partial or complete deletion of the FMR1 gene, however it most typically occurs due to amplification of a CGG triplet repeat on Xq27.3. This amplification can take 4 forms, each of whose increasing amplification correlates with varying degrees of the disease: common, intermediate, premutation and full mutation<ref name="PMID11545690 "/>.

[[File:FMR1 is silenced in FXS.jpg|thumb|250px|left|FMR1 is silenced in FXS]]

* '''Common amplification''' typically presents with anywhere between 6 and 40 repeats; 30 repeats is most common<ref>http://www.fragilex.org/html/premutation.htm</ref>. This form presents with no [[#Glossary | '''signs''']] or [[#Glossary | '''symptoms''']] of the disease.

* '''Intermediate amplification''' features between 41 and 60 repeats. Parents with intermediate amplification will similarly typically produce asymptomatic offspring. However, the risk of full mutation Fragile X Syndrome in their offspring is increased.

* '''Premutation amplification''' refers to repeats between 61-200. While children born with premutation amplification are largely asymptomatic, studies have shown that it predisposes to Parkinson's disease, intention tremor and brain atrophy, as well as ovarian failure in women<ref><pubmed>10208170</pubmed></ref><ref><pubmed>11445641</pubmed></ref><ref><pubmed>12638084</pubmed></ref>.

[[File:Fragile site appearance and distribution.jpg|thumb|200px|thumb|Fragile site appearance and distribution]]

* '''Full mutation''' refers to any amplification of >200 repeats. Children born with full mutation Fragile X Syndrome present with the classical symptoms of the disease.

Elongation of the FMR1 gene beyond 200 repeats results in methylation of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively silencing the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by methylation-induced [[#Glossary | '''chromatin''']] condensation<ref><pubmed>17477822</pubmed></ref>. Repression of FMRP expression interferes with nervous system functioning<ref>http://ghr.nlm.nih.gov/condition/fragile-x-syndrome</ref>. Studies have also suggested FMRP playing a role in synapse formation and function<ref><pubmed>12052912</pubmed></ref><ref><pubmed>18054394</pubmed></ref>, being significantly expressed in the brain and testes<ref><pubmed>8401578</pubmed></ref>. The prominence of FMR1 mRNA in the normal developing foetal central and peripheral nervous systems strongly suggests that its absence brings about the mental retardation typical of sufferers of the disease<ref><pubmed>8348153</pubmed></ref>. FMRP itself has been found to play a role in synaptic plasticity via its deactivation of gene expression by forming a complex with a RISC subunit containing Dicer enzyme<ref><pubmed>12368260</pubmed></ref><ref><pubmed>12368261</pubmed></ref>. Its role in RNA metabolism sees FMRP repressing translation of mRNA at synapses via interaction with proteins required for miRNA function<ref><pubmed>17178403</pubmed></ref>.

It is worth noting that a person with a full mutation gene may nevertheless be able to synthesise FMRP in some of their cells due to differing degrees of repeats between cells of the body, consequently presenting with milder symptoms than full mutation patients<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub2.cfm</ref>.

== Development of the Disease ==

Developmentally, mental retardation is the most common evidence of Fragile X Syndrome, with patients typically [[#Glossary | '''evincing''']] IQs of 20-70<ref><pubmed>12058838</pubmed></ref><ref><pubmed>11459752</pubmed></ref>. Nonetheless there are certain other phenotypes to be observed at various stages of development of a child with Fragile X Syndrome.

=== Fetal Development ===

During fetal development, rostral structures exhibit abnormal proportions. Facial structure reminiscent of [[#Glossary | '''macrocephaly''']] is expressed: ears, the mandible and the forehead are prominent. Given the hypothesized role of FMRP in proper neuronal development<ref><pubmed>15475576</pubmed></ref> and the role of neural crest migration in fetal facial skeleton development<ref><pubmed>14523380</pubmed></ref>, silencing of FMRP production may consequently result in imperfect neural crest migration and subsequent facial skeleton development.

=== Postnatally ===

From birth to puberty, other phenotypes of Fragile X Syndrome become evident. Impairments in working memory, selective attention, inhibition and spatial cognition begin to be exhibited as the child misses developmental milestones<ref><pubmed>18472033</pubmed></ref><ref><pubmed> 16754531</pubmed></ref>. Hoeft et al. (2010) identified a period in early brain development wherein typical neurodevelopment was not seen, correlating with observations of the above-mentioned impairments<ref><pubmed> 20439717</pubmed></ref>. Coincidentally, enlargement of the [[#Glossary | '''caudate nucleus''']] and [[#Glossary | '''thalamus''']] have been noted in such patients, a feature hypothesized to be related to inadequate repression of translation and protein expression within tissue of the central nervous system by FMRP<ref><pubmed> 21802660</pubmed></ref>.

The development of macrocephalic features continues postnatally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and postural hypotension have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyperflexibility, protruding ears and the macroorchidism evident after puberty are examples of deformities related to connective tissue dysplasia<ref name="PMID3953647"/>, which is emblematic of uncoordinated communication between cells within a tissue.

=== Postpubescent ===

Macroorchidism and mental retardation are the two main symptoms of Fragile X Syndrome evinced in postpubescent patients. From the age of 30 onwards, impairment of inhibition is significantly disparate in premutation and full mutation genotypes against a cohort of normal genotypes<ref><pubmed>18472033</pubmed></ref>, likely as a result of previously impaired neuronal development and continuing inadequate synaptic messenger degradation. Similarly, the significant levels of expression of FMRP in normal development of the testes<ref><pubmed>9259278</pubmed></ref> during puberty mean that in post-pubescent male patients, [[#Glossary | '''macroorchidism''']] is evident. Increased proliferation of Sertoli cells has been noted in these cases<ref>http://endo.endojournals.org/content/139/1/156.full</ref> and, although the exact molecular pathogenesis is as of yet unknown, FMRP’s failure in its role as a posttranscriptional regulator of mRNA export has been hypothesized to be significant either as a causative or correlative factor<ref><pubmed>17548835</pubmed></ref>.

== Signs and Symptoms ==

Fragile X syndrome is characterised by mental retardation, a variety of cognitive, physical and behavioural signs. Most males with the full FMR mutation exhibit the clinical features of fragile X displayed below. Furthermore, males affected tend not to reproduce, but this is possibly due to the severity of mental retardation.

[[File:Fragile X Phenotype.jpg|300px|thumb|Appearance of adult Fragile X Syndrome patients]]

=== Physical phenotype ===
Before puberty, children with Fragile-X tend to have no discernible differences in physical appearance. They may have a broad forehead or a slightly larger size head.
At puberty, these children begin to develop the physical signs recognized with Fragile-X, such as longer faces, larger jaws and ears<ref name="PMID2018070"><pubmed>2018070</pubmed></ref>. Furthermore, they tend to have impaired growth, and will not achieve a height that one might expect (based on familial relations, or population averages).
Males may also develop [[#Glossary | '''macroorchidism''']]: enlargement of the testicles.
Fragile-X patients may also have loose connective-tissues<ref name="PMID2195034"><pubmed>2195034</pubmed></ref>, allowing their joints to be more flexible that normal. This may cause complications arising from increased risk of [[#Glossary | '''hernia''']] as well as problems associated with other connective tissues such as: heart-valve weaknesses resulting in murmur.
Later in life, these men may develop a tremor and experience difficulty walking.

Physically, adult males often have a long narrow face, prominent ears, a prominent jaw, and macroorchidism. Other common physical features include a high arched palate, hyperextensible finger joints, double jointed thumbs, single palmar crease, hand calluses, velvet-like skin, flat feet<ref name="PMID2018070"/><ref name="PMID2195034"/>. Mitral valve prolapse has been shown to in late adolescence<ref name="PMID8464655"><pubmed>8464655</pubmed></ref>. Males with the fragile X syndrome also tend to exhibit behavioral features such as hyperactivity, social anxiety, perseverative speech and language, tactile defensiveness, stereotypes (e.g., hand-flapping), and hand biting.

=== Social interaction ===
Children with Fragile-X tend to experience social anxiety, feeling awkward and uncomfortable in new environments and situations. Often, they may avoid social interactions, due to the anxiety, and tend not to seek contact with others<ref name="PMID11773805"><pubmed>11773805</pubmed></ref>. Their anxiety often manifests itself as discontinuous speech and a lack of eye contact.

Studies into the social cognition network underlying face encoding, show profound causation relating to cortical activation <ref name="PMID18778781"><pubmed>18778781</pubmed></ref> Individuals with FXS show decreased activation of prefrontal regions that are shown to affect social cognition. These areas include the medial and superior frontal cortex. The data suggests that social anxiety in Fragile-X patients may be related to the inability to successfully activate higher level social cognition regions during the early phases of memory formation. <ref name="PMID18778781"/>

[[File:Fragile X Syndrome phenotype.png|thumb|300px|Common physical appearance of a Fragile X Syndrome Patient]]

=== Intellectual development ===
Males with FXS tend to exhibit developmental delays in childhood. By age 3, these males will test in the mentally retarded range.
As a generalisation, the majority of Fragile-X patients have an IQ defined as moderately retarded (IQ 40-54). However, the mental retardation ranges from profound (IQ<20) to mild.
Females however, show lower impairment, with only one-third having IQs within the ‘mental retardation’ range.

In sibling studies, children with Fragile-X syndrome obtain lower percentage correct scores in all subtests of the WISC (Wechsler Intelligent Scale for Children) <ref name="PMID18347972"><pubmed>18347972</pubmed></ref>. Over time, the gap between the FXS afflicted and the non-affected siblings grew dramatically. The unaffected children had a rate of intellectual development approximately 2.2x that of their FXS counterparts.

Specifically, a deficit in working memory has been attributed to the FXS mutation. When studied, they exhibit a weakness for tasks that reflect function of the central executive subcomponent of working memory<ref name="PMID19114290"><pubmed>19114290</pubmed></ref>. Furthermore, the extent of the central executive deficit is correlated significantly with larger CGG section repeat. This correlation between repeat length and working memory (specifically in asymptomatic carrier males) suggests that carrier males have greater neuropathology with larger expansions in FMR1 mRNA transcripts<ref name="PMID19114290"/>.

Generally, Fragile-X patients have trouble with forming abstract ideas, planning and problem solving. Conversely, they tend to have a good memory for pictures and visual patterns, and may be better adept at following instructions if presented in picture format.

Autistic-like behavior is also described in these males, with as many as 25% of males with the fragile X syndrome meeting the diagnostic criteria for autism.

===== Emotional characteristics =====
Fragile-X children often are easily upset or overwhelmed. New situations can easily frighten them. Upon entering an unfamiliar situation, some tend to cry, whilst others may become tense. These may often lead to tantrums or repetitive tics.
During puberty and teen years, hormone levels may exaggerate this, making the tantrums more violent and the patients largely more aggressive.
Furthermore, the usual anxiety experienced with difficult tasks may take longer to abate, meaning the patient may take longer to calm-down.

===== Language and Speech =====
Often these children have problems with coherence, word pronunciation and correct grammar use. This impairs their ability to properly communicate meaning.
More serious speech problems are associated with vocal processing, such as: moderating tone, pitch or loudness as well as coordinating the movements needed to vocalize sounds.
Furthermore, they may have difficulties processing spoken information and, as shown above, will be better at following instructions if presented in picture format.
These children may stutter, omit sounds out of their words, repeat themselves, or restart the same sentence many times. They may also speak fast and/or mumble.

It is important to note, that some of their disability to communicate can be attributed to the shyness and social anxiety, while specific deficits may be due to sensory overload, rather than specific neural problems with control of speech and language.

==Screening/Population testing==

The screening of FXS is aimed at newborns and women of reproductive age. Screening of newborns will help to recognize those affected by FXS to enable early treatment before the onset of symptoms whilst the screening of women of reproductive age is to identify those at risk of having a child born with FXS and to influence their life choices when starting a family<ref name="PMID20548240"><pubmed>20548240</pubmed></ref>.

Population screening for Fragile X Syndrome has been largely debated<ref name="PMID20548240 "/>.

'''Arguments supporting the use of population testing include:'''<ref name="PMID20548240 "/>
* The severity of the condition
* High occurrence in the general population
* The burden the condition places on the families and society as well as the individual

'''Arguments against the use of population testing include:'''<ref name="PMID20548240 "/>
* FXS is very complex resulting in a variable degree of severity
* FXS has a complicated pattern of inheritance
* The health risks associated with being a premutation carrier;
** FXTAS: Fragile X-associated tremor/[[#Glossary | '''ataxia''']] syndrome is a late onset [[#Glossary | '''neurodegenerative''']] disease. It is often encountered in older men who are carriers of the FMR1 premutation and is believed to be RNA-mediated and not due to the reduction or absence of FMRP unlike FXS<ref name="PMID19804849"><pubmed>19804849</pubmed></ref>
** FXPOI: Fragile X-associated primary ovarian insufficiency. Approximately 25% of female premutation carriers have fragile X-associated primary ovarian insufficiency<ref name="PMID19804849 "/>
** Increased risk of mild learning or emotional disabilities
* These health risks will require counseling and education
* There is a concern for the availability of resources

== Diagnosis ==

Modern-day approaches to diagnosing FXS involve the use of [[#Glossary | '''immunocytochemical''']] and molecular techniques. <ref name="PMID19099346"><pubmed>19099346</pubmed></ref> Such techniques include:

{|style="width:80%; height:100px" align="center"
|-bgcolor="lightpink"
| '''Diagnostic Technique'''
| '''Description'''
| '''Related Videos'''
|-

| valign="top" bgcolor="mistyrose"| '''Southern Blot'''
| valign="top" bgcolor="lavenderblush"|
This is known to be the most popular procedure in most laboratories as it allows for the detection of mutations and determination of methylation status in the one test. <ref name="PMID19099346 "/> For instance, Southern Blot analysis of the fragile site on the 5.1 kb EcoRl fragment revealed a “complete correlation between total methylation at a BssHll site within the CpG island and absence of FMR-1 expression in Fragile-X patients.” <ref><pubmed> 1878973</pubmed></ref>

| valign="top" bgcolor="lavenderblush"|
Southern Blot Steps [http://www.youtube.com/watch?v=6FjjjATsr50]

|-
| valign="top" bgcolor="mistyrose"|'''Modified PCR techniques'''
| valign="top" bgcolor="lavenderblush"|
An example of such modified techniques is PCR that is methylation specific. This modified PCR-based method is used for the analysis of methylation of the FMR1 gene in Fragile X patients. Methylation-specific PCR is based on the bilsulfite modification of DNA where uracil is formed by the conversion of unmethylated cytosine residues, with methylated residues remaining unconverted. “The subsequent change in the sequence of the FMR1 promoter of fragile X affected and unaffected individuals after bisulfite treatment is monitored by PCR.” <ref><pubmed> 10464640</pubmed></ref>

These techniques are an option but they are not yet as popular as other techniques for diagnosing FXS as they possess difficulty amplifying CGG repeats, interpreting results in female patients and differentiating between mosaic patterns. <ref name="PMID19099346 "/>
| valign="top" bgcolor="lavenderblush"|
Methylation-Specific PCR [http://www.youtube.com/watch?v=zgNsmY6Led4]

|-

| valign="top" bgcolor="mistyrose"| '''FMRP antibody test'''
| valign="top" bgcolor="lavenderblush"|
This test is suitable for the screening of large populations of mentally retarded people and neonates for patients with Fragile-X Syndrome who have no CGG expansion. An advantage of this test is that it is non-invasive and only requires 1 or 2 drops of blood. <ref><pubmed> 7723547</pubmed></ref> This test is still, however, not widely used. <ref name="PMID19099346"/>
| valign="top" bgcolor="lavenderblush"|
No video available for this technique
|}

Studies have shown that the most reliable method of diagnosing FXS is by '''using PCR as an initial pre-screening test followed by the Southern blot test.''' <ref name="PMID19099346"/>

== Treatment ==

Several medications have been proposed to treat the symptoms of FXS, some of which are more successful than others. However, in order to increase the efficacy of the treatments, further research and testing is imperative.

The following is a summary of the major treatment options related to specific symptoms and behavioural problems for individuals affected by FXS.

{|style="width:80%; height:100px" align="center"
|-bgcolor="lightpink"
| '''Signs & Symptoms'''
| '''Treatment Option and Description'''
|-

| valign="top" bgcolor="mistyrose"| '''Attention-Deficit/Hyperactivity Disorder (ADHD)'''

| valign="top" bgcolor="lavenderblush"|

The prevalence of ADHD symptoms in individuals with FXS is much higher than that of other individuals with either genetic conditions or non-specific intellectual disability. <ref><pubmed> 15257661</pubmed></ref> <ref><pubmed> 10865102</pubmed></ref> '''Stimulants''' have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention. <ref><pubmed> 3052064</pubmed></ref> <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

Some associated problems of using stimulants when treating symptoms of ADHD in younger children (such as 5 years of age and under) is that they may induce irritability and other behavioural problems. In this case, administration of non-stimulant medications may be more beneficial. Such alternative medications include adrenergic receptor agonists, such as '''clonidine''' and '''guanfacine'''. <ref name="PMID19117905"/>

'''Clonidine''' has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients). <ref><pubmed>15756514</pubmed></ref>

'''Guanfacine''' can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"/> <ref><pubmed> 7860456</pubmed></ref>
|-

| valign="top" bgcolor="mistyrose"|'''Mood Instability and Aggression'''

| valign="top" bgcolor="lavenderblush"|

Antipsychotic drugs, such as '''Risperidone''' and '''Aripiprazole''', are proven to be helpful in treating mood instability, aggression, perseverative behaviours and irritability in patients with FXS. <ref name="PMID19117905"/>

'''Risperidone''' was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. <ref><pubmed>14994287</pubmed></ref> “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.” <ref name="PMID19117905"/>

'''Aripiprazole''' was the second most popular atypical antipsychotic agent for targeting multiple behaviour difficulties in patients with FXS. “Typically, low doses of aripiprazole (2.5–5.0 mg for adolescents and even lower doses for younger children) work best for patients with FXS.” <ref name="PMID19117905"/>

|-

| valign="top" bgcolor="mistyrose"| '''Seizures'''

| valign="top" bgcolor="lavenderblush"|

FXS patients are known to be at an increased risk for seizures, with rates of 5% for girls and 13% to 18% for boys. <ref><pubmed>11181100</pubmed></ref> Many types of seizures have been reported in individuals with FXS; the most common type being complex partial seizures. <ref><pubmed>10448821</pubmed></ref>

A '''single anticonvulsant''' is usually the treatment of choice to control seizures in FXS. Following administration of anticonvulsant, general health and blood-specific monitoring is required. <ref name="PMID19117905"/>

|-

| valign="top" bgcolor="mistyrose"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="lavenderblush"|

Enhancement of mGluR-mediated processes and excessive mGluR5 signaling that normally would be inhibited by FMRP has been shown to contribute to many of the phenotypic features of FXS, such as cognitive deficits, behavioural abnormalities, enhanced anxiety, seizures, coordination problems and more. <ref><pubmed>15219735</pubmed></ref> <ref><pubmed>16098137</pubmed></ref> <ref name="PMID19117905"/>

'''mGluR5 antagonists''' have been studied in animal models of FXS and have demonstrated benefits in decreasing problems associated with excessive mGluR5 signaling, such as reducing seizures, enhancing cognitive skills and improving behaviour. <ref><pubmed>18093519</pubmed></ref> mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>

|-

| valign="top" bgcolor="mistyrose"| '''Behavioural Deficits'''

| valign="top" bgcolor="lavenderblush"|

Studies have shown that environmental variations impact on behaviour. For instance, fewer autistic behaviours as well as enhanced IQ scores in children with FXS are associated with a higher-quality home environment. <ref><pubmed>12548736</pubmed></ref> <ref><pubmed>11886017</pubmed></ref> Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. <ref><pubmed>11694672</pubmed></ref> Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

== Recent/ Future Research ==

=== Autism and Fragile X Syndrome (FXS) ===

Autism is a developmental disorder that usually occurs in childhood. It is part of a spectrum that is known as autism spectrum disorder (ASD).

Rapin & Tuchman, (2008),<ref><pubmed>18929056</pubmed></ref> have characterized autism into three key manifestations:

# Poor communication skills, impaired sociability and difficulty in developing relationships.
# [[#Glossary | ''' Perseveration''']], rigidity and resistance to change.
# Impairment in language, difficulty in using abstract concepts and delayed symbolic play.

[[File:Phenotypes of FXS overlap with those of Autism.jpg|thumb|310px| Phenotypes of FXS overlap with those of Autism]]

Thus it can be seen that many of the phenotypic characteristics of autism are synonymous to those of FXS, further emphasizing the interlinked nature of the two disorders.

Autism is a disorder whose etiology is not very well understood. Its diagnosis is mainly behavioral and the disorder does not present with any population-wide biomarkers. This is contrasted with FXS, a single-gene disorder whose etiology is well known and understood. Despite this difference, the two disorders share many characteristics and behavioral similarities which are suggestive of some of their commonly associated features. <ref><pubmed>17001341</pubmed></ref>

In their study on the link between FXS and autism, Hagerman et al., (2010), <ref name="PMID20858229"><pubmed>20858229</pubmed></ref> state that FXS is the most common single gene cause of autism, accounting for 2% to 6% of all autism cases. Based on the criteria of the Autism Diagnostic Observation Scale (ADOS) and the Autism Diagnostic Interview (ADI-R), on average 25-30% of males with FXS have complete autism, furthermore another 30% of boys present with a pervasive developmental disorder and the remaining FXS patients have at least one autistic characteristic, such as “poor eye contact and tactile defensiveness.” <ref name="PMID20858229"/>

It is clinically advised that all individuals diagnosed with an autism spectrum disorder should carry out the FX DNA test (involving both the Southern blot and PCR) when the etiology of their autism is ambiguous. <ref name="PMID20858229"/>

=== Fragile X Syndrome and the [[#Glossary | '''Amygdala''']] ===

Current knowledge of the cellular and molecular mechanisms underlying the symptoms of Fragile-X Syndrome is mainly centered on the studies of the [[#Glossary | '''hippocampus''']] and [[#Glossary | '''cortex''']]. However, it is known that this syndrome is also associated with strong emotional symptoms. These emotional symptoms are likely to involve changes in the amygdala. Unfortunately, the [[#Glossary | '''synaptic''']] basis of amygdala dysfunction in Fragile X Syndrome has yet to be explored. <ref name="PMID21555214"><pubmed>21555214</pubmed></ref>

A study conducted by Suvrathan and Chattarji, (2011),<ref name="PMID21555214 "/> describes recent findings from mouse models of Fragile X Syndrome. These findings have identified synaptic defects in the basolateral amygdale that are in many ways different from those found earlier in the hippocampus. This studies’ main findings reveal that “long-term potentiation and surface expression of AMPA-receptors are impaired. Further, presynaptic defects are seen at both excitatory and inhibitory synapses. Remarkably, some of these synaptic defects in the amygdala are also amenable to pharmacological rescue.” <ref name="PMID21555214 "/> Thus, future research in this area is of great importance.

These results also highlight the importance of modifying the current hippocampus-centric framework in order to more accurately explain Fragile X Syndrome-related synaptic dysfunction in the amygdala.

=== Nuclear Accumulation of Stress Response mRNAs Contributes to the [[#Glossary | '''Neurodegeneration''']] Caused by Fragile X Premutation rCGG Repeats ===
[[File:Nuclear accumulation of Hsp70 mRNA caused by Fragile X premutation rCGG repeats.png|thumb|200px| Nuclear accumulation of Hsp70 mRNA caused by Fragile X premutation rCGG repeats]]

Fragile X permutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/ataxia syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause neurodegeneration and that Pur α and hnRNP A2/B1 (rCGG repeat-binding proteins) can modulate rCGG–mediated neuronal toxicity. <ref name="PMID21655086"><pubmed>21655086</pubmed></ref>

This study conducted by Qurashi et al., (2011),<ref name="PMID21655086 "/> further explores the role of Pur α in rCGG–mediated neurodegeneration by identifying over 100 proteins that interact with Pur α, focussing on Rm62 which could modulate neurodegeneration mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 posttranscriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional mRNAs involved in stress and immune responses.” These findings are a significant part of Fragile X recent research as they suggest that the abnormal accumulation of these mRNAs in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Glossary ==

'''Allele:''' is a form of gene or genetic locus when in a group of genes. These alleles result in different observable traits such as eye colour.

'''Amygdala:''' Almond-shaped mass of grey matter located in the anterior part of the temporal lobe of the cerebellum. It is part of the limbic system and plays an important role in emotional behavior and motivation.

''' Ataxia:''' is a neurological sign and symptom that consists of a huge lack of coordination of muscle movements.

'''Caudate Nucleus:''' A nucleus in the basal ganglia which plays a role in learning and memory.

'''Chromatin:''' The combination of DNA and proteins that make up the contents of the nucleus of a cell.

'''Congenital disorder:''' A condition existing at birth or often before birth or one that develops during the first month of life.

'''Cortex:''' The outer layer of the cerebellum (i.e. cerebral cortex) while plays a key role in consciousness.

'''Cytogenetically:''' The branch of biology that deals with heredity and the cellular components, particularly chromosomes, associated with heredity.

'''Evincing:''' Be evidence of; indicate.

'''Expression:''' The production of a polypeptide as a result of gene transcription and translation.

'''Hernia:''' The protrusion of an organ or the fascia of an organ through the wall of the cavity that normally contains it.

'''Hippocampus:''' Component of the human brain located on the floor of each lateral ventricle. It is part of the limbic system and is thought to have a central role in emotion and formation of memories.

'''Immunocytochemical : ''' common laboratory technique that uses antibodies that target specific peptides or protein antigens in the cell via specific epitopes.

'''Macrocephaly:''' A condition characterised by a head of abnormally large proportions, including those of the scalp, cranium and its contents.

'''Macroorchidism:''' Abnormally large testes.

'''Metaphase:''' Stage of mitosis in the eukaryotic cell cycle (where the chromosomes separate into two identical sets in two separate nuclei) in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells.

'''Methylation:''' Chemical science of the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group.

'''Microcephaly:''' Neuro-developmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex.

'''Microphthalmia:''' Is a developmental disorder of the eye characterised by small eye/s.

'''mRNA: ''' Messenger RNA, the key transition in gene expression, translating the DNA's genetic code into the amino acids that make up proteins.

'''Neurodegeneration:''' The progressive loss of function/ structure or death of neurons within the nervous system.

''' Neurotoxin:''' a toxin or poisonous substance that acts specifically on nerve cells (neurons).

'''Nucleotide triplet:''' Is a genetic code that is a set of rules by which information encoded in genetic material (DNA or mRNA sequences) is translated into proteins; in this case it is CGG (cytosine guanine guanine).

'''Perseveration:''' Is the repetition of a particular movement, activity or response despite the cessation of a stimulus.

'''Phenotypic abnormality:''' A deviation from the normal or differing from the typical, in regards to the observable characteristics or traits of the organism.

'''Psychopedagogic:''' Combination of two main branches of study; pedagogy and psychology. Pedagogy is the study of the process of teaching and psychology is the science of behaviour and mental processes.

'''Sign:''' Objective evidence of the presence of a disease or disorder, as opposed to a symptom, which is subjective.

'''Silencing:''' Gene silencing describes the "switching off" of a gene by a mechanism other than genetic modification. That is, a gene which would usually be expressed (turned on) under normal circumstances but is switched off by machinery in the cell.

'''Symptom:''' A departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality.

'''Synaptic:''' Relating to a synapse- a junction between two nerve cells. This junction permits a neuron to transmit a chemical/ electrical signal to another cell.

'''Thalamus:''' A centrally located structure in the brain whose function includes relaying sensation, spatial sense, and motor signals to the cerebral cortex, along with the regulation of consciousness, sleep, and alertness.

'''Transcription:''' the process by which a segment of genome is read by various proteins in order to produce an mRNA strand complementary to the genome, which is then translated by ribosomes.

'''Transcription Factors:''' proteins, molecules and/or ions that assist in facilitating transcription.

'''Translation:''' The process by which mRNA produced from transcription is converted by ribosomes into polypeptides.

== References ==
<references/>

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