Embryology - User contributions [en-gb]

User:Z3290618

2011-10-19T23:43:27Z

Z3290618: /* Attendance */

{{2011Student}}

My name is Ziggy moo.

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==
===Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.===
Cytomegalovirus is an environmental teratogen that can lead to hearing loss, prenatally.

===Identify 3 factors that contribute to poor neonatal drainage of the middle ear.===
In the neonate, the auditory tube, that runs toward the nasopharynx, is almost horizontal. Whereas in the adult, it runs downward.
This tube is also far smaller and narrower prenatally, restricting the amount of fluid that can drain through it.
Finally, the auditory tube has few muscles, neonatally, that contribute to opening it. In the adult there are more.

===Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)===

MERRF - [http://www.omim.org/entry/545000 545000] MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS

==Lab Eleven==

===Name the components that give rise to the interatrial septum and the passages that connect the right and left atria===
Initially, the septum primum grows from the roof of the atrium toward the fused endocardial cushion. It stops short, producing a small channel between the atria, termed the foramen primum. Apoptosis in the body of the wall produces the foramen secundum. Simultaneously, the septum secundum grows immediately alongside the septum primum. The incomplete nature of the septum secundum gives rise to a hole, termed the foramen ovale.

===Identify the cardiac defects that arise through abnormal development of the outflow tract===
There are a number of cardiac defects arise through abnormal development of the outflow tract. Namely; Tetralogy of Fallot, Transposition of the Great Vessels, and a Double Outlet of the right ventricle.

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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.

===== 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"/>

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]
[[image:X-Linked_recessive_(affected_father).jpg|thumb|right|x-linked recessive]]
[[File:Fragile site appearance and distribution.jpg|Fragile site appearance and distribution|thumb|left|appearance]]

=== References ===
<references/>

===Content FORMATTED ONLY===

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

| valign="top" bgcolor="silver"|'''1910'''
| valign="top" bgcolor="Gainsboro"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="silver"|'''1943'''
| valign="top" bgcolor="Gainsboro"|Martin and Bell inferred and 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 '''''microcephaly''''' or '''''microphthalmia''''' <ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="silver"|'''1969'''
| valign="top" bgcolor="Gainsboro"|Herbert Lubs first documented report of 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>http://www.friendsforfragilex.org/research/history.php</ref>.
|-
| valign="top" bgcolor="silver"|'''1977'''
| valign="top" bgcolor="Gainsboro"|Sutherland showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1980'''
| valign="top" bgcolor="Gainsboro"|Turner and colleagues recognized the combination of '''''macroorchidism''''' and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1991'''
| valign="top" bgcolor="Gainsboro"|Verkerk discovered and described the FMR1 gene and encouraged the medical and '''''psychopedagogic''''' research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="silver"|'''2001'''
| valign="top" bgcolor="Gainsboro"|Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''2010'''
| valign="top" bgcolor="Gainsboro"|Paul and colleagues deduced that the elevated mRNA in FXS premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS symptoms. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|}

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

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

| valign="top" bgcolor="Gainsboro"|

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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.

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.

Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients).
Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

|-

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

| valign="top" bgcolor="Gainsboro"|

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.

Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”

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="Silver"| '''Seizures'''

| valign="top" bgcolor="Gainsboro"|

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

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="Silver"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="Gainsboro"|

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.

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. mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>
|-

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

| valign="top" bgcolor="Gainsboro"|

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. Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

--[[User:Z3290618|z3290618]] 10:57, 13 October 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:43, 20 October 2011 (EST)

User:Z3290618

2011-10-19T23:41:16Z

Z3290618: /* Lab Eleven */

2011 Group Project 5

2011-10-13T02:17:16Z

Z3290618: /* Behavioural characteristics */

{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 [[#Glossary |'''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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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.

=== Physical phenotype ===

[[File:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]
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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. The information below is found at [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks.

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

===== 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==

[[image:X-Linked_recessive_(affected_father).jpg|thumb|300px|right|Inheritance if father is affected by Fragile-X Syndrome]]

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 [[#Glossary | '''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.”

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.

[[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]]
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 ===

Fragile X premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* [http://embryology.med.unsw.edu.au/Defect/fragilex.htm Abnormal Development - Fragile X]

* [[Abnormal Development - Genetic|Abnormal Genetic Development]]

* [[Neural System - Abnormalities|Abnormal Neural Development]]

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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.

'''Synaptic plasticity:''' is the ability of the connection (synapse) between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways.

'''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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= 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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 [[#Glossary |'''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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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.

=== Physical phenotype ===

[[File:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]
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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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==

[[image:X-Linked_recessive_(affected_father).jpg|thumb|300px|right|Inheritance if father is affected by Fragile-X Syndrome]]

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 [[#Glossary | '''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.”

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.

[[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]]
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 ===

Fragile X premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* [http://embryology.med.unsw.edu.au/Defect/fragilex.htm Abnormal Development - Fragile X]

* [[Abnormal Development - Genetic|Abnormal Genetic Development]]

* [[Neural System - Abnormalities|Abnormal Neural Development]]

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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.

'''Synaptic plasticity:''' is the ability of the connection (synapse) between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways.

'''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/>

----

{{2011Projects}}

User:Z3290618

2011-10-12T23:58:20Z

Z3290618: /* Attendance */

{{2011Student}}

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==
===Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.===
Cytomegalovirus is an environmental teratogen that can lead to hearing loss, prenatally.

===Identify 3 factors that contribute to poor neonatal drainage of the middle ear.===
In the neonate, the auditory tube, that runs toward the nasopharynx, is almost horizontal. Whereas in the adult, it runs downward.
This tube is also far smaller and narrower prenatally, restricting the amount of fluid that can drain through it.
Finally, the auditory tube has few muscles, neonatally, that contribute to opening it. In the adult there are more.

===Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)===

MERRF - [http://www.omim.org/entry/545000 545000] MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS

==Lab Eleven==

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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.

===== 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"/>

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]
[[image:X-Linked_recessive_(affected_father).jpg|thumb|right|x-linked recessive]]
[[File:Fragile site appearance and distribution.jpg|Fragile site appearance and distribution|thumb|left|appearance]]

=== References ===
<references/>

===Content FORMATTED ONLY===

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

| valign="top" bgcolor="silver"|'''1910'''
| valign="top" bgcolor="Gainsboro"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="silver"|'''1943'''
| valign="top" bgcolor="Gainsboro"|Martin and Bell inferred and 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 '''''microcephaly''''' or '''''microphthalmia''''' <ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="silver"|'''1969'''
| valign="top" bgcolor="Gainsboro"|Herbert Lubs first documented report of 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>http://www.friendsforfragilex.org/research/history.php</ref>.
|-
| valign="top" bgcolor="silver"|'''1977'''
| valign="top" bgcolor="Gainsboro"|Sutherland showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1980'''
| valign="top" bgcolor="Gainsboro"|Turner and colleagues recognized the combination of '''''macroorchidism''''' and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1991'''
| valign="top" bgcolor="Gainsboro"|Verkerk discovered and described the FMR1 gene and encouraged the medical and '''''psychopedagogic''''' research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="silver"|'''2001'''
| valign="top" bgcolor="Gainsboro"|Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''2010'''
| valign="top" bgcolor="Gainsboro"|Paul and colleagues deduced that the elevated mRNA in FXS premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS symptoms. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|}

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

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

| valign="top" bgcolor="Gainsboro"|

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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.

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.

Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients).
Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

|-

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

| valign="top" bgcolor="Gainsboro"|

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.

Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”

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="Silver"| '''Seizures'''

| valign="top" bgcolor="Gainsboro"|

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

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="Silver"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="Gainsboro"|

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.

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. mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>
|-

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

| valign="top" bgcolor="Gainsboro"|

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. Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

--[[User:Z3290618|z3290618]] 10:57, 13 October 2011 (EST)

User:Z3290618

2011-10-12T23:57:39Z

Z3290618: /* Attendance */

User:Z3290618

2011-10-12T23:54:12Z

Z3290618: /* Language and Speech */

2011 Group Project 5

2011-10-12T23:52:49Z

Z3290618: /* Screening/Population testing */

{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 [[#Glossary |'''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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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.

=== Physical phenotype ===

[[File:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]
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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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==

[[image:X-Linked_recessive_(affected_father).jpg|thumb|300px|right|Inheritance if father is affected by Fragile-X Syndrome]]

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 [[#Glossary | '''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.”

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.

[[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]]
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 ===

Fragile X premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* [http://embryology.med.unsw.edu.au/Defect/fragilex.htm UNSW Embryology: Abnormal Development - Fragile X]

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://embryology.med.unsw.edu.au/Notes/neuron2.htm UNSW Embryology: Neural System - Abnormal Development]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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.

'''Synaptic plasticity:''' is the ability of the connection (synapse) between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways.

'''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/>

----

{{2011Projects}}

User:Z3290618

2011-10-12T23:36:52Z

Z3290618: /* Lab Ten */

{{2011Student}}

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==
===Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.===
Cytomegalovirus is an environmental teratogen that can lead to hearing loss, prenatally.

===Identify 3 factors that contribute to poor neonatal drainage of the middle ear.===
In the neonate, the auditory tube, that runs toward the nasopharynx, is almost horizontal. Whereas in the adult, it runs downward.
This tube is also far smaller and narrower prenatally, restricting the amount of fluid that can drain through it.
Finally, the auditory tube has few muscles, neonatally, that contribute to opening it. In the adult there are more.

===Identify 1 genetic abnormality that affects hearing development and link to the OMIM record. (Your individual abnormality should be different from all other students)===

MERRF - [http://www.omim.org/entry/545000 545000] MYOCLONIC EPILEPSY ASSOCIATED WITH RAGGED-RED FIBERS

==Lab Eleven==

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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.

===== 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"/>

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]

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

=== References ===
<references/>

===Content FORMATTED ONLY===

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

| valign="top" bgcolor="silver"|'''1910'''
| valign="top" bgcolor="Gainsboro"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="silver"|'''1943'''
| valign="top" bgcolor="Gainsboro"|Martin and Bell inferred and 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 '''''microcephaly''''' or '''''microphthalmia''''' <ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="silver"|'''1969'''
| valign="top" bgcolor="Gainsboro"|Herbert Lubs first documented report of 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>http://www.friendsforfragilex.org/research/history.php</ref>.
|-
| valign="top" bgcolor="silver"|'''1977'''
| valign="top" bgcolor="Gainsboro"|Sutherland showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1980'''
| valign="top" bgcolor="Gainsboro"|Turner and colleagues recognized the combination of '''''macroorchidism''''' and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1991'''
| valign="top" bgcolor="Gainsboro"|Verkerk discovered and described the FMR1 gene and encouraged the medical and '''''psychopedagogic''''' research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="silver"|'''2001'''
| valign="top" bgcolor="Gainsboro"|Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''2010'''
| valign="top" bgcolor="Gainsboro"|Paul and colleagues deduced that the elevated mRNA in FXS premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS symptoms. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|}

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

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

| valign="top" bgcolor="Gainsboro"|

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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.

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.

Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients).
Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

|-

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

| valign="top" bgcolor="Gainsboro"|

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.

Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”

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="Silver"| '''Seizures'''

| valign="top" bgcolor="Gainsboro"|

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

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="Silver"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="Gainsboro"|

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.

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. mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>
|-

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

| valign="top" bgcolor="Gainsboro"|

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. Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

User:Z3290618

2011-10-12T11:12:12Z

Z3290618: /* Language and Speech */

{{2011Student}}

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==
Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.
Identify 3 factors that contribute to poor neonatal drainage of the middle ear.
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 Eleven==

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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.

===== 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"/>

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]

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

=== References ===
<references/>

===Content FORMATTED ONLY===

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

| valign="top" bgcolor="silver"|'''1910'''
| valign="top" bgcolor="Gainsboro"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="silver"|'''1943'''
| valign="top" bgcolor="Gainsboro"|Martin and Bell inferred and 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 '''''microcephaly''''' or '''''microphthalmia''''' <ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="silver"|'''1969'''
| valign="top" bgcolor="Gainsboro"|Herbert Lubs first documented report of 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>http://www.friendsforfragilex.org/research/history.php</ref>.
|-
| valign="top" bgcolor="silver"|'''1977'''
| valign="top" bgcolor="Gainsboro"|Sutherland showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1980'''
| valign="top" bgcolor="Gainsboro"|Turner and colleagues recognized the combination of '''''macroorchidism''''' and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1991'''
| valign="top" bgcolor="Gainsboro"|Verkerk discovered and described the FMR1 gene and encouraged the medical and '''''psychopedagogic''''' research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="silver"|'''2001'''
| valign="top" bgcolor="Gainsboro"|Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''2010'''
| valign="top" bgcolor="Gainsboro"|Paul and colleagues deduced that the elevated mRNA in FXS premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS symptoms. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|}

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

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

| valign="top" bgcolor="Gainsboro"|

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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.

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.

Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients).
Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

|-

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

| valign="top" bgcolor="Gainsboro"|

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.

Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”

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="Silver"| '''Seizures'''

| valign="top" bgcolor="Gainsboro"|

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

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="Silver"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="Gainsboro"|

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.

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. mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>
|-

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

| valign="top" bgcolor="Gainsboro"|

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. Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

User:Z3290618

2011-10-12T11:03:55Z

Z3290618: /* Lab Ten */

{{2011Student}}

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==
Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss.
Identify 3 factors that contribute to poor neonatal drainage of the middle ear.
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 Eleven==

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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.

===== 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"/>

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]

=== References ===
<references/>

===Content FORMATTED ONLY===

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

| valign="top" bgcolor="silver"|'''1910'''
| valign="top" bgcolor="Gainsboro"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="silver"|'''1943'''
| valign="top" bgcolor="Gainsboro"|Martin and Bell inferred and 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 '''''microcephaly''''' or '''''microphthalmia''''' <ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="silver"|'''1969'''
| valign="top" bgcolor="Gainsboro"|Herbert Lubs first documented report of 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>http://www.friendsforfragilex.org/research/history.php</ref>.
|-
| valign="top" bgcolor="silver"|'''1977'''
| valign="top" bgcolor="Gainsboro"|Sutherland showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1980'''
| valign="top" bgcolor="Gainsboro"|Turner and colleagues recognized the combination of '''''macroorchidism''''' and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1991'''
| valign="top" bgcolor="Gainsboro"|Verkerk discovered and described the FMR1 gene and encouraged the medical and '''''psychopedagogic''''' research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="silver"|'''2001'''
| valign="top" bgcolor="Gainsboro"|Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''2010'''
| valign="top" bgcolor="Gainsboro"|Paul and colleagues deduced that the elevated mRNA in FXS premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS symptoms. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|}

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

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

| valign="top" bgcolor="Gainsboro"|

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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.

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.

Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients).
Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

|-

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

| valign="top" bgcolor="Gainsboro"|

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.

Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”

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="Silver"| '''Seizures'''

| valign="top" bgcolor="Gainsboro"|

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

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="Silver"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="Gainsboro"|

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.

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. mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>
|-

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

| valign="top" bgcolor="Gainsboro"|

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. Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

User:Z3290618

2011-10-12T10:57:28Z

Z3290618: /* Content Added */

{{2011Student}}

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==

==Lab Eleven==

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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.

===== 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"/>

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]

=== References ===
<references/>

===Content FORMATTED ONLY===

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

| valign="top" bgcolor="silver"|'''1910'''
| valign="top" bgcolor="Gainsboro"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="silver"|'''1943'''
| valign="top" bgcolor="Gainsboro"|Martin and Bell inferred and 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 '''''microcephaly''''' or '''''microphthalmia''''' <ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="silver"|'''1969'''
| valign="top" bgcolor="Gainsboro"|Herbert Lubs first documented report of 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>http://www.friendsforfragilex.org/research/history.php</ref>.
|-
| valign="top" bgcolor="silver"|'''1977'''
| valign="top" bgcolor="Gainsboro"|Sutherland showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1980'''
| valign="top" bgcolor="Gainsboro"|Turner and colleagues recognized the combination of '''''macroorchidism''''' and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1991'''
| valign="top" bgcolor="Gainsboro"|Verkerk discovered and described the FMR1 gene and encouraged the medical and '''''psychopedagogic''''' research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="silver"|'''2001'''
| valign="top" bgcolor="Gainsboro"|Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''2010'''
| valign="top" bgcolor="Gainsboro"|Paul and colleagues deduced that the elevated mRNA in FXS premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS symptoms. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|}

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

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

| valign="top" bgcolor="Gainsboro"|

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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.

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.

Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients).
Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

|-

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

| valign="top" bgcolor="Gainsboro"|

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.

Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”

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="Silver"| '''Seizures'''

| valign="top" bgcolor="Gainsboro"|

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

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="Silver"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="Gainsboro"|

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.

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. mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>
|-

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

| valign="top" bgcolor="Gainsboro"|

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. Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

User:Z3290618

2011-10-12T10:55:02Z

Z3290618: /* Group Page Contribution */

{{2011Student}}

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==

==Lab Eleven==

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

===Content FORMATTED ONLY===

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

| valign="top" bgcolor="silver"|'''1910'''
| valign="top" bgcolor="Gainsboro"|Thomas Hunt Morgan demonstrated that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females<ref>http://www.fragilex.org/html/history.htm</ref>.
|-
| valign="top" bgcolor="silver"|'''1943'''
| valign="top" bgcolor="Gainsboro"|Martin and Bell inferred and 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 '''''microcephaly''''' or '''''microphthalmia''''' <ref name="PMID6348096 "/>.
|-
| valign="top" bgcolor="silver"|'''1969'''
| valign="top" bgcolor="Gainsboro"|Herbert Lubs first documented report of 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>http://www.friendsforfragilex.org/research/history.php</ref>.
|-
| valign="top" bgcolor="silver"|'''1977'''
| valign="top" bgcolor="Gainsboro"|Sutherland showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1980'''
| valign="top" bgcolor="Gainsboro"|Turner and colleagues recognized the combination of '''''macroorchidism''''' and mental retardation in males in conjunction with a fragile site on the X chromosome to be a separate clinical entity<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''1991'''
| valign="top" bgcolor="Gainsboro"|Verkerk discovered and described the FMR1 gene and encouraged the medical and '''''psychopedagogic''''' research of Fragile X Syndrome<ref name="PMID19718005 "/>.
|-
| valign="top" bgcolor="silver"|'''2001'''
| valign="top" bgcolor="Gainsboro"|Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)<ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|-
| valign="top" bgcolor="silver"|'''2010'''
| valign="top" bgcolor="Gainsboro"|Paul and colleagues deduced that the elevated mRNA in FXS premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS symptoms. <ref> http://www.medlink.com/medlinkcontent.asp </ref>.
|}

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

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

| valign="top" bgcolor="Gainsboro"|

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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.

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.

Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients).
Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.” <ref name="PMID19117905"><pubmed>19117905</pubmed></ref>

|-

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

| valign="top" bgcolor="Gainsboro"|

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.

Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”

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="Silver"| '''Seizures'''

| valign="top" bgcolor="Gainsboro"|

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

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="Silver"| '''Excessive mGluR5 (metabotropic glutamate receptor 5 pathway)Signaling'''

| valign="top" bgcolor="Gainsboro"|

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.

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. mGluR5 antagonists trials are beginning with FXS individuals. <ref name="PMID19117905"/>
|-

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

| valign="top" bgcolor="Gainsboro"|

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. Educational services are also known to improve behaviour and decrease autistic symptoms in FXS patients. Higher-functioning individuals with FXS may also benefit from counseling or psychotherapy. <ref name="PMID19117905"/>

|}

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

User:Z3290618

2011-10-12T10:35:56Z

Z3290618:

{{2011Student}}

==Lab One==

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

* In 1973 the Monash University team achieved In Vitro Fertilisation (IVF). However, it only lasted a few days. On 25 July 1978, the first IVF baby was born in the UK.
Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine "for the development of in vitro fertilization"

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

* Hansen ''et al.'' (2002). The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization. ''The New England Journal of Medicine" '''342''':725-730

* In a comparison of IVF conceived, intracytoplasmic sperm injection and naturally conceived children, the rate of major birth defects was seen to be double in assisted conception. At one year of age, the ratio of birth defects in the IVF and intracytoplasmic sperm injected children was 2.0. This figure was derived after adjustment for maternal age, sex of infant etc. Before adjustment the figure was higher (9:4.2).

===''Identify 2 congenital anomalies. ''===

* Spina bifida
* Hydrocephalus

--[[User:S8600021|Mark Hill]] 09:54, 3 August 2011 (EST) You need to answer these 3 questions before Lab 2.

==Lab Two==

==Lab Three==

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

*Iodine: 400-600mg through course of pregnancy. A deficiency can cause cretinism and hypothyroidism.

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

[[File:Fragile_site_appearance_and_distribution.jpg|Fragile site appearance and distribution]]
File: Fragile site appearance and distribution

--[[User:S8600021|Mark Hill]] 23:41, 20 August 2011 (EST) Why did you upload this image as a screen shot? It has a lower resolution and may not accurately show the original image. It should have been downloaded from this page (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018726/figure/F7/) as a jpg file (CG-11-447_F7.jpg). Then renamed and uploaded to the site. Please do not use screenshots for uploading files. Repeat this exercise if you wish to get the marks for this part of the question.

==Lab Four==

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

The allantois is continuous with the Urachus to connect to the fetal bladder.

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

Ductus Arteriosus is located between the Arch of Aorta and the pulmonary artery. In adulthood, this shunt closes, forming the Ligamentum Arteriosum.
Similarly, the Foramen Ovalis allows blood to bypass the pulmonary circulation by shunting blood from the right to left atria.
The Ductus Venosus (later Ligamentum venosus) shunts fetal blood from the umbilical vein directly to the inferior vena cava.

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

I will be doing Signs and Symptoms of Fragile-X syndrome.

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

The left side is the more common for diaphragmatic hernia due the early closure of the right side of the pluroperitoneal cavity.

==Lab Six==

==Lab Seven==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?===

a) Satellite cells are not necessary for muscle hypertrophy.
b) They are however generally involved as their numbers increase during this pathology.

===Why does chronic low frequency stimulation cause a fast to slow fibre type shift?===

Under chronic low frequency stimulation, fast-twitch fibres receive the same input as slow-twitch fibres. Over a period of stimulation, the fast-twitch fibres will undergo changes in their protein structure, responding to the cronic low frequency stimulation. These protein changes will result in the fast-twitch fibres resembling the slow-twitch fibres. Effectively, giving fast-twitch fibres prolonged slow-twitch stimulation causes the shift.

===Trisomy 21 Assessment Criteria===

====The key points relating to the topic that your group allocated are clearly described.====
This has been done fairly well. The key areas of Trisomy 21 have been well described. However, I would have liked to see a section on what proteins are over produced and what genes are over transcribed due to the trisomy and how this translates into the pathology.

====The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.====
The content, headings and sub-headings are appropriate. The diagrams and graphs are useful. A better explanation is needed for some (the growth charts for example) while others have been over-used (three diagrams of the karyotype is a little excessive).

====Content is correctly cited and referenced.====
The parts that have been referenced, are referenced well. However, there is no reference for the Heart Defects section.
Furthermore, I feel there are too many large blocks of quote. The recent studies appears to all be copy + pasted as does the start of the growth charts section (though they are correctly referenced). A summary of this content would have been more appropriate.

====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.====
The wiki is clearly set out, well explained and the useful terms are defined to assist in learning. The diagrams and figures are basic, but I feel need explaining. They seem to just have been put there in order to have pictures.

====Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.====
Again, I would have preferred a gene - protein - pathology explanation. However, it appears that a lot of research has gone into the wiki.

====Relates the topic and content of the Wiki entry to learning aims of embryology.====
The wiki has been developed to illustrate the effects of Trisomy 21. No great emphasis has been placed on the development of the disorder. A stage by stage breakdown of the apparent pathology would be helpful and relate greater to the sequential nature of the embryology course.

====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.====
As written above, the wiki appears to be well researched. I would have expected more than 20 references though. The key areas of Trisomy 21 are covered and adequately "inform peers in their learning". Further depth would be appreciated. Having said that, there are links available throughout the wiki if one is interested in further research.

==Lab Eight==

===Group One===
Look of the presentation - A little work needs to be done on your formatting.
Your pictures need to be aligned with the text better. "Stats abnormal.jpg" intrudes into the text. It makes the page look a little sloppy.
Further, You have large blocks of texts that would be better put into tables to break down and simplify the information presented.

Your clinical manifestions is very basic. It looks like you have read a number of articles and just listed terms. It would be better if each manifestation was coupled with the reason for that sign/symptom. For example, write down the term, what it means and how the non-disjuntion causes it at a protein/molecular level.

Positives - Your topic is very well researched. You seem to understand and convey that understanding very well.
The body of the work is done. I would suggest looking at other pages and presenting/formatting yours so that it looks a little neater.
GOOD JOB!

===Group Two===
WOW!
This page looks fantastic. The editing is great. All of the information is presented neatly and concisely.
However, just look in "historical background" and make sure all of the lines are edited uniformly. Some have ":" some don't.
Obviously that is nothing major, I'm just nit-picking.
I think you may want to redraw your "pathology of Di George syndrome". It seems quite cluttered.

Overall: Excellent. There really isn't much to say about this page.

===Group Three===

You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

===Group Four===
The page is laid out really well. The formating is basic but effective.
Make sure your pictures are all working e.g. Mutant Huntington Disease.

===Group Six===
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

===Group Seven===

===Group Eight===

===Group Nine===

===Group Ten===

===Group Eleven===

==Lab Nine==

==Lab Ten==

==Lab Eleven==

==Lab Twelve==

==Group Page Contribution==
===Content Added===
==== 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:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]

===== 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.

===== Behavioural characteristics =====
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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.

==Attendance==
--[[User:Z3290618|z3290618]] 12:55, 28 July 2011 (EST)

--[[User:Z3290618|z3290618]] 12:38, 4 August 2011 (EST)

--[[User:Z3290618|z3290618]] 12:22, 18 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:29, 25 August 2011 (EST)

--[[User:Z3290618|z3290618]] 11:37, 1 September 2011 (EST)

--[[User:Z3290618|z3290618]] 12:50, 15 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:49, 22 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:56, 29 September 2011 (EST)

--[[User:Z3290618|z3290618]] 11:22, 6 October 2011 (EST)

2011 Group Project 5

2011-10-12T09:48:11Z

Z3290618: /* Related Links */

{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]

=== 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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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 premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* [http://embryology.med.unsw.edu.au/Defect/fragilex.htm UNSW Embryology: Abnormal Development - Fragile X]

* [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic UNSW Embryology: Abnormal Development - Genetic]

* [http://embryology.med.unsw.edu.au/Notes/neuron2.htm UNSW Embryology: Neural System - Abnormal Development]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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/>

----

{{2011Projects}}

Talk:2011 Group Project 5

2011-10-12T09:43:28Z

Z3290618:

{{2011GroupDiscussionMH}}

The images I was talking about are [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic#Genetic_Inheritance here]
The male inheritance [[image:X-Linked_recessive_(affected_father).jpg]]
It is from the wiki. I'll have to ask Mark if it is okay to use. Also, I'm going to link this page at the bottom of our page.

Hey, Jacquie just told me that YouTube lets all images to be used.
Also, I've checked those links: they aren't internal links. The embryo site isn't apart of the wiki. I have renamed them and made them look better.
I wanted to ask, how many 'drawn' pictures do we need? because, I found the male and female inheritance pictures in the UNSW Embryology site, and it is neater than ours. Thoughts?
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

Thanks Ziggy!! The picture i put up in signs and symptoms from youtube does have a clearance. It has been added to the information section of the image. --[[User:Z3290808|z3290808]]

Hey,
Nice picture in signs and symptoms. Does it have the clearance thing?
I'm going to find a photo to put up now.
I'll see if I can fix your problem with the internal links.
Also, if you want to to a signature just type out -- followed by three ~ manually and it'll work.
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

'''IMPORTANT!'''

Hey guys, i tried to do that internal link thing but it wouldn't work for me even though i tried to do it like how Dr. Hill did it.

Anyways i have put up the reference of where i want to link it to under a heading i created called "Related Links" on our group page. Could someone please try to put these two links in the correct internal link format.

Greatly appreciated, --[[User:Z3290808|z3290808]]

I have also added a new image under signs and symptoms which i have obtained from youtube. Let me know what you think. --[[User:Z3290808|z3290808]]

Just in case you guys couldn't find it!
--[[User:Z3290815|Tara Lofthouse]] 14:31, 11 October 2011 (EST)

===The final stretch!===

* The group projects will be locked after next weeks practical ('''5:00 pm''') for no further changes.
* You are free to make any changes you wish to the existing project page (additions, deletions, formatting etc).
* You should also go through all displayed uploaded files and make sure they conform to the information requirements I specified in today's practical (without the numbering):
# Correct image file name (describes what the image shows, keep it brief and to the point).
# Original legend information and any clarifying description that shows how it relates to your group topic.
# Correct citation format in its own "Reference" sub-sub-heading (if pubmed extension does not format correctly paste the entire text in and add a PMID number link at the end) You can also link to any other location of this citation, but this is not a requirement.
# The copyright information (Don't just paste, make sure it says that you can use then image).
# Finally include the student image template (copy the following in read mode, and paste in your image information in edit mode) <nowiki>{{Template:2011 Student Image}}</nowiki>

* You should complete all your updates ASAP and not leave everything to the last practical class where you will have limited time.
* We have a guest presenter for next week practical and '''I do not want any Group work during her part of the practical'''.
** Remember all edits are logged and time-stamped, I can see who has been editing when they should doing the practical.

===Last Addition to your Project Page===

* Is a new sub-heading entitled "Related Links".
* This sub-section should link to other pages on the embryology website that relate to your topic.
* Format as a bullet list, link first and a brief description (one line) of how it relates to the topic.
* An example is shown below.

==Related Links==

* [[Placodes]] - this page relates to today's practical as the earliest sensory specialisation visible on the embryo surface during week 4.

----

Hey guys, i have added some more recent/ future research into the corresponding heading! I have also added another picture under this heading. The research is very current (2011) which is good. Hope you guys like it :) --[[User:Z3290808|z3290808]] 13:37, 8 October 2011 (EST)

=== Sandra ===

SAAAAAAAAANDRA:

This is what it will look like: [[Week 2|this is how you make a link to a page on this website thingy bla]]

This is what you type in: <nowiki>[[Week 2|this is how you make a link to a page on this website thingy bla]]</nowiki>
* Where you're linking it from "Week 2"
* Description "this is how you...."

--[[User:Z3290689|z3290689]] 12:45, 6 October 2011 (EST)
----

==='''Discussion 2'''===

Hey, I'll be doing quite a few edits today/tonight. I'm putting up all of my references now.
Also, I'm going to be making sure all of our referencing is in the same format. I noticed there are a few that link the website for an article. I'll try to fix them up.
I want to just check with you guys if the following is okay:
I need to put on my student page what my contribution to the group project is. I'm going to put up "signs and symptoms" without the two pictures. The picture I put in the discussion in the first weeks (though someone else put it in the actual page) and finally the formatting for the tables (but in grey-scale as it was originally). Are there any objections for to that?
Let me know if there is anything else, and make sure you aren't accidentally editing out my edits if we're doing work :D
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

Hey guys, i have edited my diagnosis section - i have put it in a table and have found some relevant videos. Also, i will try to find some more recent research. It would be great if everyone can also pitch in to this section anytime you find some recent research that is relevant to our topic but not addressed in one of the subheadings.
To Ziggy - could you please finish off the referencing for your section Signs and Symptoms. Also if possibly, could you please add a photo to the group page. That would be much appreciated.
Cheers, --[[User:Z3290808|z3290808]] 11:59, 6 October 2011 (EST)

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_5_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_5_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

[[2011_Group_Project_5|'''Group 5''']]: [[User:z3290618]] | [[User:z3290689]] | [[User:z3290808]] | [[User:z3290815]]

----

=='''PEER REVIEW COMMENTS'''==

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
--[[User:Z3284061|z3284061]] 11:54, 29 September 2011 (EST)

'''Group 5'''

* The images might be better all on the same side
* An image is needed in Development
* "Signs and Symptoms" is a little text heavy and needs more references
* Diagnosis appears to be incomplete
* Glossary needs to be expanded
* Links to the glossary might be helpful
* Double referencing needs to be fixed
--[[User:Z3292953|z3292953]] 11:08, 29 September 2011 (EST)

Fragile X Syndrome – Group 5

* Introduction is perhaps a little brief. Some points that could be elaborated on are mentioned. Some referencing issues on the images in this section as well as a better explanation as to what these images actually show, why does the fragile x- chromosome look different?
* Screening could be its own heading and epidemiology could use more images.
* Etiology looks great. Good description in one of the images however the other one is not explained at all.
* Development of disease could use with some images, possibly the use of a table here could better summarize the information.
* Diagnosis could use more information aswell as some images.
* Recent research does not really contain much information, and I thought that the direction of future research could be commented on in this section also.
* Glossary needs completing. Some of the referencing web sites should be fixed up.

--[[User:Z3288196|Z3288196]] 10:42, 29 September 2011 (EST)

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
z3284061

Group 5:

References 5,6,7 & 8 refer to nothing. If all the information for a particular section refers to one reference, you don’t need to link to the same reference after each sentence. Just put it in once at the end of the paragraph, eg under screening/population testing and reference 11.

Good use of pictures especially at the beginning, maybe more in the middle? Also, maybe fix the formatting of the pictures as it disrupts the flow of the page and is distracting. Signs and diagnosis have few pictures making it look like a long trail of writing.

Well done with the glossary so far, but still some terms need to be added as it is incomplete at present.

z3332178 =]

peer review:

*dont like the picture positioning maybe space them out a bit?
*the first portion of history could be removed and just have like the x like description part, also how about a picture of the prson who discovered the disease?
*i think the screening part of epidemiology is irrelevent, it should just be who its affected and how many people suffer from the disease.
*text in aetiology is wquite verbose
*signs and symptoms is way to long, figure out a way to break all the text apart with pictures,tables etc
*little glossary and multiple references present
--[[User:Z3291423|Jasjit Walia]] 10:21, 29 September 2011 (EST)

'''Group 5'''

*intro: put the pictures on one side, will look more appealing and easier to read. Overall good info, easy to read.

*history: the little intro before the timeline is a little awkward and seems unnecessary. Maybe work on fixing this paragraph so it leads into the timeline instead of just talking about chromosomes, I found this abrupt. Timeline good.

*etiology: could be nice to have the images both on one side. It was a little confusing for the reader with the image on both sides.

*development: good section! But isn’t development and etiology the same thing? Maybe not put it as a heading but a subheading with etiology.

*diagnosis: third point FMRP antibody test can be the start of the point instead of writing a presentence to lead into it.

*signs, treatment: both great sections.

*glossary: is a little empty. Might want to include anything scientific like ‘chromosome’ as a normal person off the street might’nt know what that is. Also placing them in alphabetical order is helpful.

--[[User:Z3290558|z3290558]] 09:57, 29 September 2011 (EST)

'''Group 5 peer review'''

Introduction: It is a good overview of the different aspects of this disorder. Increasing the size of the hand drawn image will be good so that the writing can been seen clearly on the main page.

Epidemiology: The image is good and easy to understand. However, perhaps you should position the image next the text which talks about '...females are less likely to show severe signs...'. I think that genetic counseling and screening should be in a seperate management section. It would be ideal if Epidemiology contains more figures, especially if those numbers are in a some table.

Etiology: It would be better is you could explain what you mean by Xq27.3 in the text. I don't quite understand what you mean by '...given the location of the gene on a particularly fragile segment of Xq27.3...'. Although you have explained the figures in the text, it would be better if you add a one sentence summary of what each figure is displaying. This is because people might instinctively look at the figure first and not fully understand it and then read the text. Whereas if they looked at the figure and had some idea what it was showing and then read the text, the etiology of fragile x will be that much easier to understand. I like the size of the image because i can read it clearly.

Diagnosis: Please expand on the mechanisms of each technique. It would also be good to insert an image of each technique so that readers can know what the result of each technique looks like.

--[[User:Z3289301|z3289301]] 09:46, 29 September 2011 (EST)

'''Peer Assessment'''
*Introduction; well written but too brief. Need to include more information.
*Not sure if the 'screening' section is appropriate under the title 'epidemiology' especially because there is no inclusion of epidemiological data gathered from these tests but just explanations about their usage.
*I suggest using Microsoft word, power point or paint to draw the student drawings rather than from hand, especially images such as the one in the introduction showing X chromosome. Would look much more neater and professional.
*It also might be a good idea to hyperlink words in the text with the glossary. Makes it much more user friendly.
*The genetic section is well researched however the information is bit too confusing and the layout is messy. Try using tables to summarize the information.
*The section on 'development' of the gene is well written. Try and include imaged of patients at the different stages to compliment the writing.
*Try and incorporate a table in the 'signs and symptoms' section which is very text heavy.
*Diagnosis: section is a bit too brief. Not sure if this is possible but try and include images of these lab results characteristic of FXS in this section.
*Like the use of table in the 'treatment' section. Much more easier to read and understand.
*Glossary: needs to be expanded.
--[[User:Z3291622|Z3291622]] 09:38, 29 September 2011 (EST)

Be nice?
'''Group 5 evaluation'''

*The information in the introduction is good but it is way too brief. The other section of the page was not introduced or not introduced properly, like the diagnosis section. Adding these bits would probably make the introduction good and a bit more informative as to what to expect from the page. Also reference them.
*The history I think is fine the way it is.
*The epidemiology is good because you have touched upon the demography of the disease and its prevalence. It would have been better if you could add a bit more statistics on the geographical distribution of the disease, as it makes the section more credible than how it already is. Unfortunately I think the section from “Screening… “ onwards is not very relevant for this section. I would consider revising as to where this information should be placed under. I guess this section needs more research overall.
*The etiology is very informative and I think you have gone in-depth in the topic, and is well researched, but I think it needs some revision. The concepts were far too technical and it makes the reader a bit too confused about what the information is actually saying. The images are amazing, and if you could incorporate them in the text it would make the section better.
*The development of the disease section I think should be the pathogenesis of the disease. This section was not done properly, as I was expecting to see how the etiology and all the clinical manifestations relate to each other; instead it was all about the clinical manifestation. I think you need to look further into this section.
*The signs and symptoms section is very informative, but I am questioning the information as it is not referenced at all in most of the paragraph.
*Diagnosis should probably changed to diagnostic tests because the diagnosis is Fragile X. The information is good for introducing the techniques to the reader. I think further description of the tests is needed.
The treatment section has some very good information on it that describes the treatments used for the disease. It could probably be better if you could highlight the actual treatments and make it stand out.
*Recent research is a bit disappointing because the most recent research that were presented is 3 years ago. As a reader, this makes me question the content of the page, whether it is up-to-date or not. It would also be good to have a more recent paper/research and the inclusion of future direction of this disease.
--[[User:Z3290841|z3290841]] 10:24, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*The lone sentence at the beginning of the history is unnecessary.

:*Essay language such as “for example” is a bit out of place on a wiki page. Tailor language to a web page.

:*In the epidemiology section some statements are not referenced. Where are these ‘examples’ coming from?

:*Research section would benefit from the bolding of paper headings or authors names.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:13, 29 September 2011 (EST)

'''Group 5 peer Review'''
* Introduction has good information, but it needs to be more catchy for readers to want to read onto the page.
* the first line of the history section seems not to be so greatly relevant to the history section. Also in the table there’s a 30 year gap at the start of the table. No important things happened during this time?
* I don’t think the information for ‘Screening/Population testing’ is necessary to be put under the epidemiology section, rather under diagnostics.
* Explanation about the genetic location of the mutation should be given. Also information found under aetiology should be re-formatted so it is easier to read.
* The development of disease section has good information. Would it be possibly to accompany these sections with images.
* Some parts under signs and symptoms are not referenced properly as it is lacking the referencing. Also possibly include some more pics/graphs/audio/movies in this section to accompany the text.
*Diagnosis section must be expanded upon. It has potential as concepts are there but more info could be included.
* Nice use of a table in the treatments section
* the paragraph starting with: ‘’ Autism is a disorder whose etiology is not…’’ should be placed to flow with the first sentence in the recent research section. It will make the paragraph flow better.
*acronym for ‘’ Autism Diagnostic Interview (ADI-R)’’ seems bit odd, what does the R stand for?
* if possible add an article from 2011 in the recent research section to make it though you are showing the reader the most cutting edge research in this field.
*Glossary must be expanded upon, many words have not yet been included.
* In the referencing section the referencing is done well. I did notice a repetition in the referencing in reference number 37 and 38. Please fix up.
* More images are needed on the page to get the image and text ration right, especially towards the middle of the page.
*other than that good page people.

--[[User:Z3291317|Z3291317]] 08:44, 29 September 2011 (EST)

Group 5

*Introduction - ok except it was a bit hard to read with the text squeezed between the two images located left and right, maybe both images could be placed on one side, such as the right, to make it easier to read and add to the continuity and flow of the page. There is a lot that could be expanded on to add to the introduction, maybe a brief explanation of the FMR1 gene and the phenotypic manifestations as a result of it being silent.
*Etiology, not really sure but i don’t think you’ve referred to the images included here, formatting could be improved with both images being on one side
*Development of the Disease – very nice heading, information easy to follow and well referenced, best heading on this page, great job.
*Signs and Symptoms – another very well organised section
*Diagnosis – this section could be best suited to a table, making each technique easy to identify and define.
*Treatment – great use of a table, information is very clear and easy to understand.
*Glossary – more terms need to be added, such as the acronyms used throughout the page: ADHD, CGG, PCR, FXS, etc.

--[[User:Z3331469|z3331469]] 07:01, 29 September 2011 (EST)

'''Group 5 Peer Review'''

• Generally good sub-heading structure. The overall flow is consistent (nice pink tables!), however I think it could be tidied up more, for example; images placed on the right hand side of the page.

• Double up’s in references need to be removed.

• Introduction is brief and concise, good!

• Epidemiology could be improved by the addition of a table, and maybe the ‘Screening/Population testing’ section could be a sub-heading on its own.

• The first paragraph in the genetic contribution of Aetiology I feel could be worded better, but nice images and really good description of the cause of the abnormality.

• Development of the disease is a really good explanatory section, really informative! The addition of images here, would really improve it (if able to find them)

• More images needed in the signs and symptoms section. Also maybe the addition of a table to sum up the different signs and symptoms with the different age groups would help. This section seems incomplete to me, where are all your references?

• Diagnosis needs some more detail and possibly an image (for completion)

• The ‘signs and symptoms’ in the Treatment section aren’t really consistent/parallel with the ‘signs and symptoms’ section itself. This could be improved by adding a similar table in the signs and section sub-heading outlining the same ‘signs and symptoms’ (just an idea)

• Glossary needs a lot more definitions.

--[[User:Z3289829|z3289829]] 02:43, 29 September 2011 (EST)

*Intro: Like the hand drawn figure but it’s not explained and most importantly, the Image is not referenced at all. Define methylation perhaps- it’s not a good idea to have introduction with a lot of terminology because you will lose your audience if they can’t understand the initial part f the page. The description of features is brief and good way to introduce the disease, it would help if you could use an image of an affected patient instead of the chromosome (which can be sued in the etiology section)/

*History: Love the colour but perhaps add a few more events, it looks very short. You can link your bolded words to a glossary.

*Epidemiology: The “screening” section doesn’t belong here. The section explained in dot points is not referenced at all. The image is great, but there is no references to the original image or any explanation of the image itself. Genetic counselling subheading also doesn’t belong in this section.

*Etiology: Clear and easy to follow but there are words that need defining in the glossary. The section would benefit if the image of the chromosome was moved here. Perhaps more explanation on the FMR gene. The first image could do with a bit more explanation. There are words in there eg: 5UTR that are not easy to understand.

*Development of disease: Good, the subheadings help and its well-formatted. Need a picture explaining the development.

*Signs and symptoms: The image is great, you can use this as your introduction to make it a bit more engaging. You should also make it bigger and explain the distinguishing features. The research is thorough!

*Diagnosis: Very short, needs more detail.

*Treatment: Love the colour, very detailed

*Glossary: Needs a lot more work! There are many words that you will need to define. For example “ allele, permutation, asymptomatic...” list goes on.

*Reference: What’s happening in references 3-8? That’s not proper referencing format. Number 41 reference – a link isn’t a reference.

*Overall: You keep referring to the disease as either fragile X syndrome or FXS. It’s best to stick to one or the other to avoid confusion. Need more interesting images. Some excellent research but it could do with a bit of work. Good job so far.

--[[User:Z3290270|z3290270]] 02:31, 29 September 2011 (EST)

'''Group 5'''

Introduction: Good pictures but they need to be bigger. Also, this section seems like a brief summary of the sections to come. I think it would be good if you included some more general background information on fragile x.

History: This section could be longer. The table would look good with some pictures in it.

Epidemiology: Great section and I like the diagram but some of the words in the diagram are hard to read.

Genetics: This section is reasonably well explained. The genetic terms need more explaining though.

Development: Good section but needs some pictures.

Signs and symptoms: Great section. Well written, flows well and easy to understand. Needs more pictures though.

Diagnosis: This section seems a bit short. Maybe you could explain how the diagnostic techniques work.

Treatment: The table seems too text heavy. Maybe add some pictures to break up the text.

Recent research: overall, good section. --[[User:Z3291324|z3291324]] 23:23, 28 September 2011 (EST)

Group 5

Hi, I can see some progress on this page which is good, content is interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: What is FMR1 gene? Need more information here, as in when was it first discovered, some stats
#* Epidemiology: I think screening information is extensive enough to be a section on its own
#* Etiology: no explanation of FMR1 gene so far, what is its normal function? Also, please refer to images used in this section
#* Development of the disease:nice succinct, easy to follow section. Perhaps add an image for one of the stages mentioned here?
#* Signs: REFERENCING!!! But, content is good and interesting
#* Diagnosis: An image here would be nice, and an explanation of how the technology is used to diagnose FXS
#* Treatment: Nice table with good information
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to balance out the text and image ratio, some good subheadings
#Content is correctly cited and referenced.
#* poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* I feel more research needs to be done here
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#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.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* Although the content is here, there is still a lot of work needed to make this page feel complete
* glossary is very lacking in terminology
* need more images
* further research would be nice to explain this disease in more detail

--[[User:Z3291643|z3291643]] 22:56, 28 September 2011 (EST)

'''Group 5:'''

•The introduction lacks referencing and is a little short, but good use of the images to gain the attention of the reader though as I was reading it I would have preferred for the images to both be on the right hand side.

•The student drawn image on the right is not explained very well and does not contain the correct copyright information.

•Is the diagnosis section finished? It seems a little short and lacking in detail, maybe add some more information to this section, perhaps also an image to help build up this heading and make it more balanced with the other sections.

•Glossary is incomplete and should be in alphabetical order

•References are repeated, but good work on the research

•Overall I liked the formatting of the page, it is easy to read visually appealing and a good use of images to balance out the text.

--[[User:Z3332183|z3332183]] 21:28, 28 September 2011 (EST)

'''Group 5'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there and well described.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Future research is well researched, but is there any other research possibilities that are on going to show breath of research? Glossary needs to be expanded - FXS as an acronym needs to be put there. Table in treatment has too much text. Put the text outside the table and use the table to summarise the content. The information in diagnosis is too brief and could go into a table. Consider expanding that section and provide more information on how and why the techniques diagnoses FXS.

'''*Content is correctly cited and referenced.'''
File:Fragile site appearance and distribution.jpg needs to be correctly referenced. Duplication of references need to be fixed. Emotional characteristics, Language and Speech, Physical phenotype and Physical phenotype section needs references.

'''*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.'''
no explanation given for File:Fragile x chromosome..jpg. more images would be good (Eg: in Fetal Development section maybe include an image of what a fetus looks like who has FXS?)

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Decent reference list and good in-text citation but is missing referencing in some areas.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Fetal development detailed.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has followed the guidelines but some changes would be good.

--z3329495 21:17, 28 September 2011 (EST)

'''GROUP 5: Fragile X Syndrome'''
*Info in the intro is ok but could be improved by maybe including more of an explanation of the CGG codon (some may not know what a codon is and what this implicates) and a small sentence on FMR1 gene
*The placement of the two images in the introduction is a bit weird, it disrupts the end of this paragraph. Consider just putting them on the same side or putting one of them in a different section
*I don't think the first sentence of the history section is history related, looks like it could be better placed in the intro
*Timeline is ok but could possibly be researched more to include more dates, but it's good that it goes up to 2010
*I don't know if Screening/Population testing goes under epidemiology, i think it's more part of management/diagnosis
*Etiology info appears clear and concise, maybe the image of the gene would be better placed in this section
*I find the section development of disease informative and summarised well. I like the way it's structured (subheadings are fitting), an image could improve this section
*Signs and symptoms looks like its been researched extensively, info is comprehensive and summarised well, a graph or another image could improve this section and balance out the text
*Physical phenotype has no referencing (where did this info come from?)
*Diagnosis is very underdeveloped, a lot more explanation is needed for these diagnostic techniques, images could also help improve this section
*Treatment is well researched, use of a table here is suitable, however maybe you could break up the writing by splitting up the Treatment Option and Description into two different sections of the table
*Recent Research is ok, a good intro paragraph may improve this section, maybe provide more recent developments

Overall:
*Glossary is incomplete and many words need explaining, consider linking the highlighted words to the glossary as an improvement, also it might be a good idea to include acronyms in the glossary as well
*legends of images could be expanded a little more
*Reference list needs some work, I don't think links to websites are the proper way to reference

--[[User:Z3331556|z3331556]] 21:15, 28 September 2011 (EST)

'''Peer Assessment Group 5-Fragile X Syndrome'''
*The introduction contains a little bit of heavy info in it. You might want to introduce the complex concepts e.g.methylation of the CGG triplet so the reader can ease into the page.
*The absence of references in the introduction makes it feel unreliable.
*The History seems to be succinct, good work.
*Nice diagram in 'Epidemiology', however it is missing a description and copyright information
*Avoid the italics as it makes the page look inconsistent as you dont have italics very often throughout
*'Development of Disease' is divided well into distinct sub headings, easy to follow
*'Signs and Symptoms' is heavy with too much information, can you summarize some of it to condense the whole section. Also maybe consider finding some images to give it a better balance.
*'Diagnosis' requires a little more explanation of what is involved in the different types of methods.
*The table in 'Treatment' needs division of the second column maybe into treatment option and a separate description just to make it look less heavy
*'Recent Research' is structured nicely, makes it a lot easier to read
*The definitions in 'Glossary' are inadequate
*Avoid italics in the glossary
*The reference list needs some major reformatting
--[[User:Z3308968|Tahmina Lata]] 19:43, 28 September 2011 (EST)

'''Group 5: Peer Assessment'''
* Your page looks a bid 80's with all the different pinks in your table. Not a bad thing, however may be just one colour per table would be enough
* The introduction is too brief and written a little careless and lacks referencing.
* The history table is good in the way that it's chronologic and easy to read but you could write a bid more about the relevance of these events.
* Your drawing needs some copyright information and if the writing would have more contrast it would come more into account.
* The aetiology section is informative overall but some long sentences could be separated and more explanatory. Put the pictures on the same side may be to give it a bid more shape.
* The development of the disease section and signs and symptoms section read well and there is good use of subheadings.
* Is there some current research you could talk about?
* Your glossary and your references clearly need some editing and fixing up
* Overall your page seems to be written a bid careless but there are bids of interesting information in there. --z3279511 17:10, 28 September 2011 (EST)

'''Peer Assessment #5'''
*Intro looks funny with a pic on each side of the text – reconsider this formatting. Maybe both on one side and one under the other?
*Intro 1st para is very detailed for an intro- perhaps explain it more, or in more general terms. The detail will come later
*The intro sentence in history would be better in the intro.
*You keep referring to the FMR1 gene, but I have no idea what this is or how it is relevant. Please explain it somewhere! Maybe have a short para just on it and explain about it.
*In signs and symptoms, are ‘emotional characteristics’ and ‘language and speech’ meant to be their own subheadings, or subheadings of ‘intellectual development’?
*Diagnosis section is not complete, needs a lot more info and explanation of the techniques, how they work, why they are used/relevant. – Modified PCR section is too wordy.
*Treatment table is good, can you stretch it so it takes up the whole box instead of being centered? Would look better
*Recent research – surely there is more you can discuss/other areas?
*I’m sure everyone else has mentioned it, but the glossary needs work. Really, just define lots of the ‘big’ words, as you can’t assume everyone knows what they all mean.
--[[User:Z3332824|z3332824]] 11:59, 28 September 2011 (EST)

''' Group 5 Peer Assessment'''
* First student figure has no explanation as to what it's all about, and is a pretty simple diagram. What does it contain? Where is your copyright information? The same can be said with the second student-drawn figure. Make sure this is fixed!
* The introduction section appears to be pretty short. Try to keep away from using the brackets and just enter your information in a continuous format.
* The headings and subheadings work quite well. However, the lack of images in the signs and symptoms section make this difficult to read; it seems like a large block of text without anything to assist in the breakup of the page (making it difficult to read and easy for us to lose attention).
* Subheadings are used quite well. The treatment section is well presented in table format, but once again, any images to help break things up?
* The recent and future research section doesn't seem to be completed. Is there anything that can be done for the future of the disease? Is it related to any other disease processes? The glossary also seems short and isn't in alphabetic order. Please add all the terms to the glossary to ensure that there is completeness of the project! There are many terms that are difficult to understand, so slot them in here.
* There just needs to be more work done overall to ensure that the project flows smoothly and all the smaller details are accounted for. At the moment there is still a large part of the project that feels quite sketchy and requires more work.
--[[User:Z3288827|Leonard Tiong]] 10:33, 28 September 2011 (EST)

Group 5: Fragile X
*Introduction: Maybe a bit too concise, some of the content that should be in the intro is missing. Maybe this should be redone with references! Also, it doesn’t draw the reader’s attention unfortunately.
*History: Simple table, but a small explanation regarding the significance of the discoveries would be very helpful.
*Epidemiology: Nice picture, had to tilt my head a little. The “Screening/Population testing” seems like a whole new section itself. Might have to look into that?
*Etiology: This section was very well managed.
*Development: I like the subheadings, maybe an image to help add some visuals, but not required.
*Signs and Symptoms: This again, was well done, though detailed, the mass text was slightly disorientating, another image perhaps?
*Diagnosis: Looks incomplete, more info required, probably another sub-heading would do.
*Treatment: Best section in this webpage. Detailed and neatly laid out.
*Glossary: Some explanations and a few more words added here would do the trick!
*Overall: The basic fundamentals are there, some more info here, and a few tweaks there is all that is needed! Keep it up.
--[[User:Z3332327|Lisa Xiao]] 01:25, 28 September 2011 (EST)

'''Group 5'''

*Introduction should be explained a little better and also referenced
*Hand drawn image needs the correct referencing/copyright info
*Good use of subheadings in epidemiology
*Etiology is a little hard to follow
*Development of disease needs an image to break up the text
*Signs and symptoms is very text heavy- try to change it up a bit i.e. use of dot points
*Good use of table in treatment
*Glossary needs to be extended
*Overall, this has potential to be a good project with a few adjustments

'''Group 5'''

*Introduction: too much detail, give an overview. Only one of the images would be enough.

*History: well done

*Epidemiology: screening / population testing should be a separate section, very good image

*Etiology: well done,

*Development and Symptoms: both sections are clear and easy to follow, good use of subheadings

*Diagnosis: seems incomplete

*Treatment: very detailed

*Research: I would add some other examples. If you want to outline only autism, maybe change the heading.

*Glossary: there is a lot missing

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 21:31, 27 September 2011 (EST)

'''Group Peer assessment'''
*Introduction images placement may work better on one side or below the information though current placement is confusing affecting text as well.
*History requires more elaboration as well at least indication of the founder in the introduction of the history even an image of the founder would benefit this section, although the timeline is nicely done.
*Development and disease would be better as a sub heading under eitology as development of the disease links with the causation of the disease.
*Glossary needs work done as most terms are genetic related and those without a genetic background will find difficulty understanding the web page.
*Referencing only needs to adjust the links, links need to be sited properly manually.
z3332250 23:50, 26 September 2011 (EST)

Group 5 Peer Review

*Introduction does not entice the reader to read the rest of the page. Maybe less scientific language in the introduction?
*Table under history is well presented and visually appealing
*“Postnatally” and “postpubescent” need to have “development” added to the subheadings
*Well referenced
*The consistent colour scheme throughout is a nice touch
*Another image under signs and symptoms would make this section look more balanced
*Diagnosis seems brief-add information or perhaps merge with another subheading
*Glossary needs to be expanded
*Logical, clear and organised structure
*Overall, a good page. The bulk of it is there. If each section just changed some minor things, this page would improve greatly.
--[[User:Z3308965|Fleur McGregor]] 19:38, 26 September 2011 (EST)

'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it could be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

--Z3389806 07:34, 26 September 2011 (EST)

'''Group 5 Critique'''

#• Introduction should not contain clinical manifestations. It should introduce the topic as a whole. This section needs to be re-written
#• The history section is ok. The timeline could be explained a little better to give a clearer view of what the history of the disease is to the reader
#• Epidemiology should not contain the advantages and disadvantages of population testing. This should be another section in itself
#• Aetiology was fine
#• Development of the disease was ok
#• Signs and Symptoms was good
#• Diagnosis needs to be more detailed than what it is
#• Treatment and recent research is impressive
#• Glossary needs more terms added to it. It is too short, however that will be fixed when you add more explanations to the other sections and define the terms here.

--[[User:Z3289991|Robert Klein]] 18:57, 24 September 2011 (EST)

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

* I liked your page as it had a simple and easy-to-follow lay out
* Some of the images could have been made larger on your actual page just so that it adds dynamics to your page
* I was left wanting to know more about the diagnosis, this section was quite brief
* I personally found your treatment table hard to read because there was so much information. Personally I believe that maybe dot-point form could have been used to get your main points across.
* Perhaps expand upon your glossary as there were some words that weren’t in there that maybe should have been.
--[[User:Z3332629|z3332629]] 15:25, 22 September 2011 (EST)

'''Group 5 Assessment'''
*The Fragile X Chromosme. Jpg needs both an explanation and referencing.
*There is no referencing in the Introduction section. Where did you get this information from?
*History- Good idea to setup using a chart to organize the data. First time I’ve seen that.
*Fragile X Inheritance jpg looks great!!! Way to incorporate the data into a figure. However, it does still need citing.
*Not all the information in the Screening/Test Population is cited. Where is this information referenced from?
*The Development of Disease portion could use a figure or two to make it more appeasing to look at.
*Some of the information under Signs and Symptoms is also not cited. Where was this information drawn from?
*Good chart under the treatment section. However, maybe try a bullet list on the right hand column to help set the ideas apart from each other?
*The glossary link seems a little short… Are you sure there aren’t any more words which would be helpful to define for the audience?
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
*Overall, good work! Just work on the referencing and some of the visual aspects.
--[[User:Z3391078|Z3391078]] 15:09, 27 September 2011 (EST)

Group 5
* Straight into it hey- a little bit more of an “introduction” might help sorry. The first line kind of scared me. Yes it is relevant information but I think you need to almost ‘warm the reader up’ if you know what I mean. When reading anything I don’t think jumping straight into the nuts and bolts of how it works benefits anyone. I think you should start with what it is and why it is important that the reader learns about your topic
* The history section is brief and I don’t actually understand the relevance of the discoveries. While putting the information in a table shows that you know how to format it to look pretty, it is not the most effective way of showing
* Your hand drawn images still need to be referenced and copyright put on them
* Reading through I am overwhelmed by the content. This may be due to a lack of proper introduction or early explanation. I feel like the information isn’t as accessible as it could be
* Development of the disease would work well in a table I think
* Maybe put the clinical manifestations into dot points? I just feel like everything is a bulk of text and it would be better if you broke it up a little
* An image in diagnosis would help
* Treatment works well in a table
* Glossary could be extended
* You are on the right tract it is just a very heavy project. The content is all there but I found it really hard to get through.

'''Group 5'''
* Great structure with headings and subheadings, very easy to follow and read.
* Nice succinct intro. good over view of the disease. - Maybe you could dot point phenotypic abnormalities
* Some areas a little text heavy, additional pictures would fix this problem. for example some more pictures in signs and symptoms.
* Good simple history, well researched. easy to follow.
* Maybe Screening/Population testing could be its own heading.
* Great section on development of disease! I like the format very interesting relevant information! well done!
* Treatment section well put together but a little text heavy- try condensing info or bullet points.
* Make sure all the pictures are referenced properly.
* Nice to see your references grouped.
* NIce student drawn picture.
* Make sure all your acronyms/ scientific lingo is in the glossary.
* I liked that you has a continuous colour scheme for your tables. It makes your page look very neat.
* The bottom of the page is a little text heavy.

*'''Introduction''': Concise and to the point.
*'''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.
*'''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.
*'''Screening/Population testing''': Looks fine.
*'''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.
*'''Development''': Well explained, good use of subheadings.
*'''Signs and Symptoms''': Also well explained, good use of subheadings.
*'''Diagnosis''': Too short. What about non-genetic diagnosis?
*'''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?
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?
*'''Glossary''': Too short, more terms need to be explained.
*'''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.
*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?

'''Group Project 5'''

*The introduction was too in detail and did not seem like an introduction. Also there are no references ?
*the history is easy to read
*Etiology - very nice section of information
*Development of the Disease - was a good idea to put this in and the information is easy to read, maybe include some hyperlinks to the glossary?
*The treatment table is quite informative and easy to read due to its structure and quite appealing to the eyes
*More should be added to the glossary

--[[User:Z3330313|z3330313]] 20:02, 28 September 2011 (EST)

'''Peer Assessment: Group Project 5'''
*The introduction has no references.
*More pictures in the sections on development, signs and symptoms and diagnosis would help to make the written work easier to follow. Examples of pictures that could be added are images of neural crest development put in the development section or images of diagnostic techniques in the section on diagnosis.
*The section on treatment is clear and informative.
*The different diagnostic procedures could be explained more, such as how they are each conducted.
*Instead of having the uncommon words highlighted in bold, maybe you could link the words to their definition down in the glossary section.
*Some of the references are duplicated. They can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
*In conclusion, this project is both accessible to people who have no great scientific knowledge, but also delves into quite specific knowledge. A good balance.
--[[User:Z3217345|z3217345]] 21:59, 27 September 2011 (EST)

'''Peer Review'''

* the layout was not well structured
* was able to understand the disorder

--[[User:Z3060621|z3060621]] 21:31, 28 September 2011 (EST)

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{{2011GroupDiscussionMH}}

=='''Discussion'''==

Hey,
I'm under the impression that he is closing it tomorrow at 5pm.
Also, make sure you aren't editing stuff out. (Tara, im looking at you :P you edited out some of my stuff, but it's all good).
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

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'''BORIS!'''
This is what you missed in todays lab: you need to read through the peer review comments and work on the comments that are applicable to your section (although you don't have to agree with all the comments), it is also now time to work on all the sections together and we still need more pictures (make sure they are referenced properly and include the student template - if we have any material not cited properly, Mark is going to delete it), we also need to look into maybe adding videos to our page and Sandra would like us all to contribute to the recent research section. We have 2 weeks to finalise our wiki and our page will be closed at 11am two Thursdays from now. Thanks!

--[[User:Z3290815|Tara Lofthouse]] 19:13, 29 September 2011 (EST)

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Collins SC, Coffee B, Benke PJ, Berry-Kravis E, Gilbert F, et al. (2010) Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype. PLoS ONE 5(3): e9476. doi:10.1371/journal.pone.0009476

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Nice work Sandra! I will keep looking and i see you changed your table to pink too haha --[[User:Z3290815|Tara Lofthouse]] 20:54, 18 September 2011 (EST)

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Hey guys, i have just edited our group page and put up 3 pictures! Please try to find more before Monday (especially under development of the disease and signs and symptoms as these parts are so dense with writing and thus need pictures to break it up a little bit)! Cheers, --[[User:Z3290808|Sandra Issa]] 00:24, 18 September 2011 (EST)

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Here:

http://3.bp.blogspot.com/-88xXtruHpyo/TlaALBe6CaI/AAAAAAAABx8/ZMdZULFKEns/s1600/happy%2Bcamper.jpg

{|
|-
| Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)
| 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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.
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.
Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients). Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.”
|-
| Treatment of Mood Instability and Aggression
| 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.
Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”
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.”

|}

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Hey guys, yep i will be there at 10 count me in! --[[User:Z3290808|z3290808]] 09:42, 15 September 2011 (EST)

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It looks like it is going to be late nights all round. We should try and pump out an intro in that time tomorrow as well as at least one image? --[[User:Z3290815|Tara Lofthouse]] 18:52, 14 September 2011 (EST)

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Okay, Tomorrow at 10am it is. I'll finish my stuff off tonight (it looks like being a late night :P).
I'm assuming that it doesn't have to be perfect by tomorrow. It just needs to look alright, so that people can give us feedback before we finish it, yeah?
Also, Boris, Interview is on the 27th. I was just visiting a friend. I'll tell you how it goes though, when it does happen. --[[User:Z3290618|Ziggy Harrison-Tikisci]] 17:43, 14 September 2011 (EST)
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I can make it at 10am on Thursday as well --[[User:Z3290815|Tara Lofthouse]] 12:08, 14 September 2011 (EST)

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Ooo, interview? How'd it go?
I don't have time to meet up today (Wednesday), but I can see you guys in the lab at 10 tomorrow, before the class.
--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)

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Hey Guys, Sorry I've been in Melbourne for the week, so haven't done any work. Getting on it now. Going to do all my referencing, editing etc.
Wanted to ask if there is a time when we can get together, go through it all and make it pretty. Did we just want to do this before our lab on thursday, or if you guys have some time on wednesday afternoon?
Furthermore, how harsh is the criticism/feedback? Doesn't mince his words, does he? --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:51, 12 September 2011 (EST)

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Hey Boris yes i am experiencing the same problem. I cannot see the references and the reference list looks like a bunch of arrows facing superiorly. I got a bit worried but then checked the other groups and they had the same issue. I'm not sure what we can do? Let me know. ---[[User:Z3290808|Sandra Issa]] 09:49, 9 September 2011 (EST)

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WHAT HAPPENED TO OUR REFERENCES. Can you guys do me a favour and tell me if you can see them? I was trying to put in an image just then and when I did the save it came up with references wiped. I tried undoing my last edit to no avail. There are still 30 something references, there's just nothing IN them. When I finished my word edit earlier today I actually saved the ENTIRE script as a word document; when I tried to rewrite EVERYTHING with that same (working) script it still came up with stuffed up references.

Let me know if you guys see the same problem. If you do, I'll have to get in contact with Mark Hill to fix the script.
--[[User:Z3290689|Boris Zolotarev]] 23:31, 8 September 2011 (EST)

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I hate how the times shown on the editing thing are totally out of whack....can I post anything up at the moment? ><
--[[User:Z3290689|Boris Zolotarev]] 23:27, 7 September 2011 (EST)

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Hey guys, i have just added the diagnosis part of our page and have also finished the treatment. Let me know if you think the treatment is too long? Or if you want to make any changes to the "Recent Research" part of our page.

Also, i will add in more references for this part very soon. I have put in a general reference (review article) but will make sure i include all references used very soon.

Have a good night, --[[User:Z3290808|Sandra Issa]] 21:16, 7 September 2011 (EST)

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Suggestion: rename '''Development of disease''' to '''Progression of disease'''. Also, I should have a heap up later tonight, I'm compiling it all in a separate document at the moment.

--[[User:Z3290689|Boris Zolotarev]] 15:39, 7 September 2011 (EST)

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Hey guys, just letting you know that i have found a great article which addresses many current 'treatments' for FXS. Also, i have found another article which summarises the current methods of diagnosing FXS. I will add this information (what i think is most relevant from the articles) onto our group page under the headings "treatment" and "diagnosis" '''very soon'''. Please feel free to add in anything that you believe i have not addressed under these headings. Also, i will try to edit our page as a whole soon so that it looks more uniform in appearance. Over the next couple of days we should all read each of the sections and try to add in additional information that someone else may have missed. Also, a reminder to keep an eye out for relevant pictures that have unrestricted access to add onto our page!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:32, 5 September 2011 (EST)

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Hey, I'm doing a whole bunch now. I'll properly reference it all later, but I'm getting a lot of it off the american National Institute of Health. They've got references for all of it. So when I have more time, I'll go through those references, add them, and edit the information. So, what I put on the group page will just be an overview. Also, you people should go to bed earlier :)
http://www.nichd.nih.gov/publications/pubs/fragileX/sub6.cfm
--[[User:Z3290618|z3290618]] 09:49, 1 September 2011 (EST)

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z3290808: I don't know why it wouldn't let you save, i wasn't editing at that time. Try again and if it doesn't work maybe paste your work here with your references and one of us can put it onto the project page for you?

Boris: At least something is up :) My section needs a lot more editing and a lot more cross checking with other references as well.. Any progress is good progress at the moment
--[[User:Z3290815|Tara Lofthouse]] 03:35, 1 September 2011 (EST)

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Heya, I took a stab at my section but I'm a bit dead at the moment '''(points to timestamp)'''. I'll try get some more done tomorrow between the lecture and lab.

On the plus side, I added another 6 or 7 references to our thingy ^^

--[[User:Z3290689|Boris Zolotarev]] 01:28, 1 September 2011 (EST)

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Guys it's not letting me save what i have written onto the group page! Is anyone currently on and trying to edit at this same time?
--[[User:Z3290808|z3290808]] 22:41, 31 August 2011 (EST)

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Yo Boris, You do Etiology, I'll do signs and symptoms. We can work towards the middle.
That leaves history and epidemiology to Tara and Recent research to Sandra. And then we can all refine it/make an intro.
We can at least do that to start with.
Also: can everyone contribute to the glossary. If you find any terms that people (eg. me) wont understand, please keep them.--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:10, 25 August 2011 (EST)

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The only reason why we need to put our names down now is to satisfy the weekly individual assessment but of course we can change things. Just put your name down for epidemiology or whatever was left over and we'll discuss it tomorrow. Maybe if we could get to the lab 10-15min earlier because we never get enough time at the end of the lab?

--[[User:Z3290815|Tara Lofthouse]] 19:50, 24 August 2011 (EST)

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Just skimmed through this (damn I left it late >< ), should I nominate something now or should we discuss it tomorrow?
Also, what do you guys think of having some sort of realtime chat method? Facebook or something of the sort...
--[[User:Z3290689|Boris Zolotarev]] 19:17, 24 August 2011 (EST)

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Yeah i know but the ones i put my name down for are really not that lengthy. We definitely need to have a chat tomorrow.
--[[User:Z3290815|Tara Lofthouse]] 17:45, 24 August 2011 (EST)

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Hey guys, you haven't left much for Boris and i to do lol .. I don't mind doing the recent research part - focussing on autism and fragile x.. but then i don't know what Boris would do? I will sign my name for now but i think we will have to change it around a little to better make the work load equally spread.

Cheers, --[[User:Z3290808|Sandra Issa]] 16:17, 24 August 2011 (EST)

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I've taken it all on board and changed it. I'm fine for you to do whatever you want but doing both the genetic component and the signs and symptoms might be a lot of work. As long as everything is spread evenly i don't mind :)

--[[User:Z3290815|Tara Lofthouse]] 16:35, 23 August 2011 (EST)

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Hey, I was wondering if anyone minds if I do 'Genetic contribution'. Also, is it okay if I follow the timeline of the disease? I will start with the chromosome, saying what the defect causes at a molecular level, and then when it first presents, and how it affects the development etc up until how it presents in the adult. Which means I'd probably do "Signs and symptoms (clinical Presentation)" as well.
ALSO, we need to do a brief history of the disorder. So, below I've just tweaked the layout Tara and Sandra put up: let me know what you think

* Introduction
* History of Disease
* Epidemiology
* Etiology
** Genetic contribution
* Development of Disease
** Fetal Development
** At birth
** In Adult
*** Signs and symptoms
* Recent research
** Fragile X and Autism
** Diagnosis
** Treatment
--[[User:Z3290618|z3290618]] 15:18, 23 August 2011 (EST)

----

Yeah, i think it makes sense how you've got it Sandra. However like Boris said maybe instead of having the heading "Autism and Fragile X Syndrome" maybe we could have recent research/current studies or something along those lines and include it there along with diagnosis and treatment? Do you think that etiology is too similar to genetic contribution?

ALSO!!!
What headings would you like to research? I set up a "Who's doing what?" heading on this page to sign your name next to.

--[[User:Z3290815|Tara Lofthouse]] 12:39, 23 August 2011 (EST)

----

Hey guys, i have come up with a couple of headings that we can use:

* Introduction (short summary)
* Epidemiology
* Signs and Symptoms (Clinical Presentation)
* Etiology
* Genetic Contribution
* Autism and Fragile X syndrome
* Diagnosis?
* Treatment?
* References

Tara i also like the format that you have included below.. i basically have made something similar but in different order based on what i think should come first perhaps? The ones with a question mark beside them are ones that i am unsure if we should include or not. Let me know what you think!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:03, 23 August 2011 (EST)

----

Hahaha of course it's your place to say so.. good suggestion, i'll fix it up now and if we want to change it again than that's no problem. I just thought i'd put something up to get started and we can go from there. What i've done is no where near completed.
--[[User:Z3290815|Tara Lofthouse]] 18:52, 22 August 2011 (EST)

----

(I know it's not my place to say so before I've submitted my own suggestion but) I think I'd put "Autism and Fragile X Syndrome" within the "recent research" subtopic. I'll put up a suggestion by tomorrow evening, if not earlier.
--[[User:Z3290689|Boris Zolotarev]] 09:27, 22 August 2011 (EST)

----

'''Hello everyone,''' what do you think about using the following headings for our project? Are there ones that you think we could omit or ones that you would like to add? We also need to decide on who is doing what.
* Signs and symptoms
* Diagnosis
* Genetics
* Etiology
* Epidemiology
* Treatment
* Recent research
** Autism and Fragile X Syndrome
* References

--[[User:Z3290815|Tara Lofthouse]] 16:26, 21 August 2011 (EST)

----

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Lab_2_-_Group_Project Group project] --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:58, 4 August 2011 (EST)

[http://www.ncbi.nlm.nih.gov/omim OMIM]--[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:59, 4 August 2011 (EST)

----

Here's another interesting topic.

[http://en.wikipedia.org/wiki/Apert_syndrome Apert Syndrome aka acrocephalosyndactyly] --[[User:Z3290689|z3290689]] 11:38, 11 August 2011 (EST)

=='''Congenital Hypomyelinating Neuropathy'''==

What do you guys think you of this topic [http://omim.org/entry/605253 Congenital Hypomyelinating Neuropathy]?

There are quite a few articles on it:

Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination.

Analysis of congenital hypomyelinating Egr2 Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination.

P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves.

Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg–Hirschsprung disease: Phenotypes linked by SOX10 mutation.

A lot of them overlap with their findings and the focus of their studies, so it seems to be a pretty thorough topic.

--[[User:Z3290689|Boris Zolotarev]] 21:03, 7 August 2011 (EST)

----

I’m all for doing '''Congenital Hypomyelinating Neuropathy''' as our topic.

Here are some articles I have found:

'''Research Articles:'''

[http://neuro.cjb.net/content/29/8/2312.full.pdf+html Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure in Mice Carrying the Egr2 I268N Mutation]

* 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

[http://jnnp.bmj.com/content/48/12/1269.full.pdf Congenital hypomyelinating neuropathy]

* 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:'''

[http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TBD-3W37BMX-C-1&_cdi=5140&_user=1975841&_pii=S0887899498001386&_origin=&_coverDate=03%2F31%2F1999&_sk=999799996&view=c&wchp=dGLzVzb-zSkWA&md5=d2e9e64dfc821d71ec81675f01932b8a&ie=/sdarticle.pdf Congenital hypomyelinating neuropathy: two patients with long-term follow-up]

* 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

--[[User:Z3290815|Tara Lofthouse]] 12:22, 9 August 2011 (EST)

----

=='''Fragile X Syndrome'''==

==='''Articles'''===

Hey guys,
I had a look at Congenital Hypomyelinating Neuropathy and to be honest i did not find it very appealing. I found the disorder "Fragile X Syndrome" to be very interesting! Can you guys please check out the following link on [http://www.fragilex.org/html/cause.htm/ Fragile X Syndrome] and let me know if the disease also interests you!? I found the information on it is quite extensive and the disease is well known. If you do not want to base our project on this syndrome, i am sure we can decide on one we can all enjoy studying! :)

Here are some interesting articles that i have found on '''Fragile X Syndrome''':

* '''Review Article''': Fragile X syndrome: from gene discovery to therapy <ref><pubmed>21196228</pubmed></ref>

- This review focuses on the molecular and biochemical pathways shown to be relevant in the Fragile X Syndrome. It describes that a mutation in the FMR-1 gene was found to lead to Fragile X Syndrome due to excessive repeats of the trinucleotide sequence CGG which is known to inactivate the FMR-1 gene, making the X chromosome fragile and prone to breakage. This review article also demonstrates the many vital functions of the FMR-1 gene such as its role in RNA transport and stability, thus absence of the protein transcribed and translated from this gene is thought to affect brain development and thus leads to signs of mental retardation.

* '''Research Article:''' DNA methylation represses FMR-1 transcription in fragile X syndrome <ref><pubmed>1301913</pubmed></ref>

- This research article explores the two molecular differences of the FMR-1 gene in normal individuals vs. those with Fragile X Syndrome. These differences are an increase in size of an FMR-1 exon containing a CGG repeat and abnormal methylation of a CpG island 250 bp proximal to this repeat. This research article also shows how these two abnormalities repress transcription of the FMR-1 gene, leading to the absence of the FMR-1 protein which is thought to be the contributing factor to the Fragile X phenotype.

--[[User:Z3290808|Sandra Issa]] 19:53, 9 August 2011 (EST)

----

Here are some articles I have found for '''Fragile X syndrome''':

'''Research Article:''' The state of synapses in Fragile X Syndrome <ref><pubmed>19325170</pubmed></ref>

* Fragile X Syndrome is the most common inherited form of mental retardation and a leading genetic cause of autism.

* Evidence that suggests alterations in synapse number, structure and function are associated and contribute to both Fragile X Sydrome and autism.

* Fraile X Syndrome is caused by loss of function of the Fmr1 gene which encodes the RNA binding protein, FMRP (FMRP is present at synapses where it associates with mRNA and polyribosomes).

* FMRP is also has a role in synapse development, elimination and plasticity.

* An understanding of the molecular and synaptic function of FMRP, as well as the consequences of its loss, has led to the early developments of therapeutic strategies for Fragile X Syndrome.

'''Research Article:''' Fragile x syndrome: history, diagnosis, and treatment. <ref><pubmed>6348096</pubmed></ref>

'''Review Article:''' Systematic review of pharmacological treatments in fragile X syndrome <ref><pubmed>19822023</pubmed></ref>

'''Review Article:''' FMR1 and the fragile X syndrome: human genome epidemiology review <ref><pubmed>11545690</pubmed></ref>

--[[User:Z3290815|Tara Lofthouse]] 14:37, 16 August 2011 (EST)

----

==='''Images'''===

[[File:FMR4 is silenced in fragile X syndrome.jpg|thumb|FMR4 is silenced in fragile X syndrome]]

[[File:FMR4 is silenced in fragile X syndrome.jpg|350px]]

File:FMR4 is silenced in fragile X syndrome

--[[User:Z3290808|Sandra Issa]] 10:20, 14 August 2011 (EST)

----

[[File:Hippocampal_Formation.jpg‎|thumb|Hippocampal_Formation]]

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

File: Hippocampal_Formation

--[[User:Z3290815|Tara Lofthouse]] 13:49, 17 August 2011 (EST)

----

Like?
[[File:Fragile site appearance and distribution.png|300px]]
File: Fragile site appearance and distribution
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 08:55, 18 August 2011 (EST)

----

[[File:Journal.pone.0013559.g001.png‎|thumb|FXR1 (A) and FXR2 (B) crystal structures]]

[[File:Journal.pone.0013559.g001.png‎|300px]]

File: FXR1 and FXR2 crystal structures

--[[User:Z3290689|Boris Zolotarev]] 11:00, 18 August 2011 (EST)

== '''Who's doing what?''' ==

* Introduction = DO AT THE END!!!!
* History of Disease = Tara
* Epidemiology = Tara
* Etiology = Boris
** Genetic contribution<ref>http://www.fragilex.org/html/premutation.htm</ref><ref><pubmed>10208170</pubmed></ref><ref><pubmed>11445641</pubmed></ref><ref><pubmed>12638084</pubmed></ref><ref>http://ghr.nlm.nih.gov/condition/fragile-x-syndrome</ref><ref><pubmed>8348153</pubmed></ref>
** Development of Disease
*** Fetal Development
*** At birth
*** In Adult
* Signs and symptoms = Ziggy
** Physical phenotype
** Social interaction
**Intellectual development
* Recent research = Sandra
** Fragile X and Autism
** Diagnosis
** Treatment
* References

==ZIGGY'S STUFF==
Just leaving this here for the next hour, so that I don't have to retype it all (can't get wifi in the embryo lab).

The hallmark of the fragile X syndrome is mental retardation, which was noted as early as 1943 in a report of a large family with 11 mentally retarded males and two mildly retarded females. 64 The clinical phenotype associated with the syndrome has since been widened to include a variety of cognitive, physical, and behavioral characteristics (reviewed in Mazzocco). 65 Almost all males with the full mutation exhibit some clinical features of the fragile X syndrome. Also, most affected males do not reproduce, presumably due to the severity of mental retardation. With regard to cognitive function, affected males often exhibit developmental delay very early in childhood. By the age of 3 years, most males will test in the mentally retarded range. 66 Ultimately, almost all males with the fragile X syndrome are mentally retarded, with severity ranging from profound (IQ <20) to mild mental retardation (IQ 50–70), with most being moderately retarded (IQ 40–54) (reviewed in Hagerman). 67 Physically, adult males often have a long narrow face, prominent ears, a prominent jaw, and macroorchidism (reviewed in Hagerman). 67 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, and mitral valve prolapse (reviewed in Warren and Sherman). 8 Males with the fragile X syndrome also tend to exhibit behavioral features such as hyperactivity, social anxiety, perseverative speech and language, tactile defensiveness, stereotypies (e.g., hand-flapping), and hand biting (reviewed in Hagerman). 67 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. 68 The association of fragile X with autism, however, is not clear because the proportion of males with the fragile X syndrome meeting the diagnostic criteria for autism seems to diminish with age. 68

Physical phenotype
Before puberty, children with Fragile-X tend to have no discernable 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. 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 macro-orchidism: enlargement of the testicles. Fragile-X patients may also have loose connective-tissues, allowing their joints to be more flexible that normal. This may cause complications arising from increased risk of 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.

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. Their anxiety often manifests itself as discontinuous speech and a lack of eye contact.

Results indicate that compared to the control group, individuals with FXS exhibited decreased activation of prefrontal regions associated with complex social cognition, including the medial and superior frontal cortex, during successful face encoding. Further, the FXS and control groups showed significantly different relationships between measures of social anxiety (including gaze-fixation) and brain activity during face encoding. These data indicate that social anxiety in FXS may be related to the inability to successfully recruit higher level social cognition regions during the initial phases of memory formation.
Reference: Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome.

Intellectual development
As a generalisation, the majority of Fragile-X patients have an IQ between 1 and 2 standard deviations below the population mean. This equates to around 40-85. Few Patients lie out-side this range, with approximately 20% within the ‘normal’ range (85-115) and less below 40. Females however, show lower impairment, with only one-third having IQs within the ‘mental retardation’ range.
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.
Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points.

Studies of intellectual function in FXS often demonstrate a mean IQ decline of 4 to 9 standardized points over intervals ranging from several months to 13 years.
Reference: Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Working Memory
First, when individuals affected by the premutation are examined as a group, they exhibit a weakness only for tasks that reflect functioning of the central executive subcomponent of working memory.

Second, when both permutation sub-groups are examined together, the extent of the central executive deficit is significantly correlated with larger CGG repeat expansions.

For permutation males who are asymptomatic, mild executive dysregulation, inhibitory deficits that worsen with age, and declarative verbal learning and memory are notable.

The detection of a deficit in the central executive component of working memory in the fourth decade of life that progressively deteriorates with age suggests a cumulative process that may be a cognitive correlate to the underlying degenerative process identified in premutation males.

The significant correlation between CGG repeat length and central executive working memory in asymptomatic carrier males suggests greater neuropathology in carrier males with larger expansions in FMR1 mRNA transcripts.
Reference: Lifespan changes in working memory in fragile X premutation males

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.

== '''References''' ==
<references/>

Talk:2011 Group Project 5

2011-10-12T08:54:43Z

Z3290618:

{{2011GroupDiscussionMH}}

Hey, Jacquie just told me that YouTube lets all images to be used.
Also, I've checked those links: they aren't internal links. The embryo site isn't apart of the wiki. I have renamed them and made them look better.
I wanted to ask, how many 'drawn' pictures do we need? because, I found the male and female inheritance pictures in the UNSW Embryology site, and it is neater than ours. Thoughts?
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

Thanks Ziggy!! The picture i put up in signs and symptoms from youtube does have a clearance. It has been added to the information section of the image. --[[User:Z3290808|z3290808]]

Hey,
Nice picture in signs and symptoms. Does it have the clearance thing?
I'm going to find a photo to put up now.
I'll see if I can fix your problem with the internal links.
Also, if you want to to a signature just type out -- followed by three ~ manually and it'll work.
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

'''IMPORTANT!'''

Hey guys, i tried to do that internal link thing but it wouldn't work for me even though i tried to do it like how Dr. Hill did it.

Anyways i have put up the reference of where i want to link it to under a heading i created called "Related Links" on our group page. Could someone please try to put these two links in the correct internal link format.

Greatly appreciated, --[[User:Z3290808|z3290808]]

I have also added a new image under signs and symptoms which i have obtained from youtube. Let me know what you think. --[[User:Z3290808|z3290808]]

Just in case you guys couldn't find it!
--[[User:Z3290815|Tara Lofthouse]] 14:31, 11 October 2011 (EST)

===The final stretch!===

* The group projects will be locked after next weeks practical ('''5:00 pm''') for no further changes.
* You are free to make any changes you wish to the existing project page (additions, deletions, formatting etc).
* You should also go through all displayed uploaded files and make sure they conform to the information requirements I specified in today's practical (without the numbering):
# Correct image file name (describes what the image shows, keep it brief and to the point).
# Original legend information and any clarifying description that shows how it relates to your group topic.
# Correct citation format in its own "Reference" sub-sub-heading (if pubmed extension does not format correctly paste the entire text in and add a PMID number link at the end) You can also link to any other location of this citation, but this is not a requirement.
# The copyright information (Don't just paste, make sure it says that you can use then image).
# Finally include the student image template (copy the following in read mode, and paste in your image information in edit mode) <nowiki>{{Template:2011 Student Image}}</nowiki>

* You should complete all your updates ASAP and not leave everything to the last practical class where you will have limited time.
* We have a guest presenter for next week practical and '''I do not want any Group work during her part of the practical'''.
** Remember all edits are logged and time-stamped, I can see who has been editing when they should doing the practical.

===Last Addition to your Project Page===

* Is a new sub-heading entitled "Related Links".
* This sub-section should link to other pages on the embryology website that relate to your topic.
* Format as a bullet list, link first and a brief description (one line) of how it relates to the topic.
* An example is shown below.

==Related Links==

* [[Placodes]] - this page relates to today's practical as the earliest sensory specialisation visible on the embryo surface during week 4.

----

Hey guys, i have added some more recent/ future research into the corresponding heading! I have also added another picture under this heading. The research is very current (2011) which is good. Hope you guys like it :) --[[User:Z3290808|z3290808]] 13:37, 8 October 2011 (EST)

=== Sandra ===

SAAAAAAAAANDRA:

This is what it will look like: [[Week 2|this is how you make a link to a page on this website thingy bla]]

This is what you type in: <nowiki>[[Week 2|this is how you make a link to a page on this website thingy bla]]</nowiki>
* Where you're linking it from "Week 2"
* Description "this is how you...."

--[[User:Z3290689|z3290689]] 12:45, 6 October 2011 (EST)
----

==='''Discussion 2'''===

Hey, I'll be doing quite a few edits today/tonight. I'm putting up all of my references now.
Also, I'm going to be making sure all of our referencing is in the same format. I noticed there are a few that link the website for an article. I'll try to fix them up.
I want to just check with you guys if the following is okay:
I need to put on my student page what my contribution to the group project is. I'm going to put up "signs and symptoms" without the two pictures. The picture I put in the discussion in the first weeks (though someone else put it in the actual page) and finally the formatting for the tables (but in grey-scale as it was originally). Are there any objections for to that?
Let me know if there is anything else, and make sure you aren't accidentally editing out my edits if we're doing work :D
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

Hey guys, i have edited my diagnosis section - i have put it in a table and have found some relevant videos. Also, i will try to find some more recent research. It would be great if everyone can also pitch in to this section anytime you find some recent research that is relevant to our topic but not addressed in one of the subheadings.
To Ziggy - could you please finish off the referencing for your section Signs and Symptoms. Also if possibly, could you please add a photo to the group page. That would be much appreciated.
Cheers, --[[User:Z3290808|z3290808]] 11:59, 6 October 2011 (EST)

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_5_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_5_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

[[2011_Group_Project_5|'''Group 5''']]: [[User:z3290618]] | [[User:z3290689]] | [[User:z3290808]] | [[User:z3290815]]

----

=='''PEER REVIEW COMMENTS'''==

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
--[[User:Z3284061|z3284061]] 11:54, 29 September 2011 (EST)

'''Group 5'''

* The images might be better all on the same side
* An image is needed in Development
* "Signs and Symptoms" is a little text heavy and needs more references
* Diagnosis appears to be incomplete
* Glossary needs to be expanded
* Links to the glossary might be helpful
* Double referencing needs to be fixed
--[[User:Z3292953|z3292953]] 11:08, 29 September 2011 (EST)

Fragile X Syndrome – Group 5

* Introduction is perhaps a little brief. Some points that could be elaborated on are mentioned. Some referencing issues on the images in this section as well as a better explanation as to what these images actually show, why does the fragile x- chromosome look different?
* Screening could be its own heading and epidemiology could use more images.
* Etiology looks great. Good description in one of the images however the other one is not explained at all.
* Development of disease could use with some images, possibly the use of a table here could better summarize the information.
* Diagnosis could use more information aswell as some images.
* Recent research does not really contain much information, and I thought that the direction of future research could be commented on in this section also.
* Glossary needs completing. Some of the referencing web sites should be fixed up.

--[[User:Z3288196|Z3288196]] 10:42, 29 September 2011 (EST)

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
z3284061

Group 5:

References 5,6,7 & 8 refer to nothing. If all the information for a particular section refers to one reference, you don’t need to link to the same reference after each sentence. Just put it in once at the end of the paragraph, eg under screening/population testing and reference 11.

Good use of pictures especially at the beginning, maybe more in the middle? Also, maybe fix the formatting of the pictures as it disrupts the flow of the page and is distracting. Signs and diagnosis have few pictures making it look like a long trail of writing.

Well done with the glossary so far, but still some terms need to be added as it is incomplete at present.

z3332178 =]

peer review:

*dont like the picture positioning maybe space them out a bit?
*the first portion of history could be removed and just have like the x like description part, also how about a picture of the prson who discovered the disease?
*i think the screening part of epidemiology is irrelevent, it should just be who its affected and how many people suffer from the disease.
*text in aetiology is wquite verbose
*signs and symptoms is way to long, figure out a way to break all the text apart with pictures,tables etc
*little glossary and multiple references present
--[[User:Z3291423|Jasjit Walia]] 10:21, 29 September 2011 (EST)

'''Group 5'''

*intro: put the pictures on one side, will look more appealing and easier to read. Overall good info, easy to read.

*history: the little intro before the timeline is a little awkward and seems unnecessary. Maybe work on fixing this paragraph so it leads into the timeline instead of just talking about chromosomes, I found this abrupt. Timeline good.

*etiology: could be nice to have the images both on one side. It was a little confusing for the reader with the image on both sides.

*development: good section! But isn’t development and etiology the same thing? Maybe not put it as a heading but a subheading with etiology.

*diagnosis: third point FMRP antibody test can be the start of the point instead of writing a presentence to lead into it.

*signs, treatment: both great sections.

*glossary: is a little empty. Might want to include anything scientific like ‘chromosome’ as a normal person off the street might’nt know what that is. Also placing them in alphabetical order is helpful.

--[[User:Z3290558|z3290558]] 09:57, 29 September 2011 (EST)

'''Group 5 peer review'''

Introduction: It is a good overview of the different aspects of this disorder. Increasing the size of the hand drawn image will be good so that the writing can been seen clearly on the main page.

Epidemiology: The image is good and easy to understand. However, perhaps you should position the image next the text which talks about '...females are less likely to show severe signs...'. I think that genetic counseling and screening should be in a seperate management section. It would be ideal if Epidemiology contains more figures, especially if those numbers are in a some table.

Etiology: It would be better is you could explain what you mean by Xq27.3 in the text. I don't quite understand what you mean by '...given the location of the gene on a particularly fragile segment of Xq27.3...'. Although you have explained the figures in the text, it would be better if you add a one sentence summary of what each figure is displaying. This is because people might instinctively look at the figure first and not fully understand it and then read the text. Whereas if they looked at the figure and had some idea what it was showing and then read the text, the etiology of fragile x will be that much easier to understand. I like the size of the image because i can read it clearly.

Diagnosis: Please expand on the mechanisms of each technique. It would also be good to insert an image of each technique so that readers can know what the result of each technique looks like.

--[[User:Z3289301|z3289301]] 09:46, 29 September 2011 (EST)

'''Peer Assessment'''
*Introduction; well written but too brief. Need to include more information.
*Not sure if the 'screening' section is appropriate under the title 'epidemiology' especially because there is no inclusion of epidemiological data gathered from these tests but just explanations about their usage.
*I suggest using Microsoft word, power point or paint to draw the student drawings rather than from hand, especially images such as the one in the introduction showing X chromosome. Would look much more neater and professional.
*It also might be a good idea to hyperlink words in the text with the glossary. Makes it much more user friendly.
*The genetic section is well researched however the information is bit too confusing and the layout is messy. Try using tables to summarize the information.
*The section on 'development' of the gene is well written. Try and include imaged of patients at the different stages to compliment the writing.
*Try and incorporate a table in the 'signs and symptoms' section which is very text heavy.
*Diagnosis: section is a bit too brief. Not sure if this is possible but try and include images of these lab results characteristic of FXS in this section.
*Like the use of table in the 'treatment' section. Much more easier to read and understand.
*Glossary: needs to be expanded.
--[[User:Z3291622|Z3291622]] 09:38, 29 September 2011 (EST)

Be nice?
'''Group 5 evaluation'''

*The information in the introduction is good but it is way too brief. The other section of the page was not introduced or not introduced properly, like the diagnosis section. Adding these bits would probably make the introduction good and a bit more informative as to what to expect from the page. Also reference them.
*The history I think is fine the way it is.
*The epidemiology is good because you have touched upon the demography of the disease and its prevalence. It would have been better if you could add a bit more statistics on the geographical distribution of the disease, as it makes the section more credible than how it already is. Unfortunately I think the section from “Screening… “ onwards is not very relevant for this section. I would consider revising as to where this information should be placed under. I guess this section needs more research overall.
*The etiology is very informative and I think you have gone in-depth in the topic, and is well researched, but I think it needs some revision. The concepts were far too technical and it makes the reader a bit too confused about what the information is actually saying. The images are amazing, and if you could incorporate them in the text it would make the section better.
*The development of the disease section I think should be the pathogenesis of the disease. This section was not done properly, as I was expecting to see how the etiology and all the clinical manifestations relate to each other; instead it was all about the clinical manifestation. I think you need to look further into this section.
*The signs and symptoms section is very informative, but I am questioning the information as it is not referenced at all in most of the paragraph.
*Diagnosis should probably changed to diagnostic tests because the diagnosis is Fragile X. The information is good for introducing the techniques to the reader. I think further description of the tests is needed.
The treatment section has some very good information on it that describes the treatments used for the disease. It could probably be better if you could highlight the actual treatments and make it stand out.
*Recent research is a bit disappointing because the most recent research that were presented is 3 years ago. As a reader, this makes me question the content of the page, whether it is up-to-date or not. It would also be good to have a more recent paper/research and the inclusion of future direction of this disease.
--[[User:Z3290841|z3290841]] 10:24, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*The lone sentence at the beginning of the history is unnecessary.

:*Essay language such as “for example” is a bit out of place on a wiki page. Tailor language to a web page.

:*In the epidemiology section some statements are not referenced. Where are these ‘examples’ coming from?

:*Research section would benefit from the bolding of paper headings or authors names.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:13, 29 September 2011 (EST)

'''Group 5 peer Review'''
* Introduction has good information, but it needs to be more catchy for readers to want to read onto the page.
* the first line of the history section seems not to be so greatly relevant to the history section. Also in the table there’s a 30 year gap at the start of the table. No important things happened during this time?
* I don’t think the information for ‘Screening/Population testing’ is necessary to be put under the epidemiology section, rather under diagnostics.
* Explanation about the genetic location of the mutation should be given. Also information found under aetiology should be re-formatted so it is easier to read.
* The development of disease section has good information. Would it be possibly to accompany these sections with images.
* Some parts under signs and symptoms are not referenced properly as it is lacking the referencing. Also possibly include some more pics/graphs/audio/movies in this section to accompany the text.
*Diagnosis section must be expanded upon. It has potential as concepts are there but more info could be included.
* Nice use of a table in the treatments section
* the paragraph starting with: ‘’ Autism is a disorder whose etiology is not…’’ should be placed to flow with the first sentence in the recent research section. It will make the paragraph flow better.
*acronym for ‘’ Autism Diagnostic Interview (ADI-R)’’ seems bit odd, what does the R stand for?
* if possible add an article from 2011 in the recent research section to make it though you are showing the reader the most cutting edge research in this field.
*Glossary must be expanded upon, many words have not yet been included.
* In the referencing section the referencing is done well. I did notice a repetition in the referencing in reference number 37 and 38. Please fix up.
* More images are needed on the page to get the image and text ration right, especially towards the middle of the page.
*other than that good page people.

--[[User:Z3291317|Z3291317]] 08:44, 29 September 2011 (EST)

Group 5

*Introduction - ok except it was a bit hard to read with the text squeezed between the two images located left and right, maybe both images could be placed on one side, such as the right, to make it easier to read and add to the continuity and flow of the page. There is a lot that could be expanded on to add to the introduction, maybe a brief explanation of the FMR1 gene and the phenotypic manifestations as a result of it being silent.
*Etiology, not really sure but i don’t think you’ve referred to the images included here, formatting could be improved with both images being on one side
*Development of the Disease – very nice heading, information easy to follow and well referenced, best heading on this page, great job.
*Signs and Symptoms – another very well organised section
*Diagnosis – this section could be best suited to a table, making each technique easy to identify and define.
*Treatment – great use of a table, information is very clear and easy to understand.
*Glossary – more terms need to be added, such as the acronyms used throughout the page: ADHD, CGG, PCR, FXS, etc.

--[[User:Z3331469|z3331469]] 07:01, 29 September 2011 (EST)

'''Group 5 Peer Review'''

• Generally good sub-heading structure. The overall flow is consistent (nice pink tables!), however I think it could be tidied up more, for example; images placed on the right hand side of the page.

• Double up’s in references need to be removed.

• Introduction is brief and concise, good!

• Epidemiology could be improved by the addition of a table, and maybe the ‘Screening/Population testing’ section could be a sub-heading on its own.

• The first paragraph in the genetic contribution of Aetiology I feel could be worded better, but nice images and really good description of the cause of the abnormality.

• Development of the disease is a really good explanatory section, really informative! The addition of images here, would really improve it (if able to find them)

• More images needed in the signs and symptoms section. Also maybe the addition of a table to sum up the different signs and symptoms with the different age groups would help. This section seems incomplete to me, where are all your references?

• Diagnosis needs some more detail and possibly an image (for completion)

• The ‘signs and symptoms’ in the Treatment section aren’t really consistent/parallel with the ‘signs and symptoms’ section itself. This could be improved by adding a similar table in the signs and section sub-heading outlining the same ‘signs and symptoms’ (just an idea)

• Glossary needs a lot more definitions.

--[[User:Z3289829|z3289829]] 02:43, 29 September 2011 (EST)

*Intro: Like the hand drawn figure but it’s not explained and most importantly, the Image is not referenced at all. Define methylation perhaps- it’s not a good idea to have introduction with a lot of terminology because you will lose your audience if they can’t understand the initial part f the page. The description of features is brief and good way to introduce the disease, it would help if you could use an image of an affected patient instead of the chromosome (which can be sued in the etiology section)/

*History: Love the colour but perhaps add a few more events, it looks very short. You can link your bolded words to a glossary.

*Epidemiology: The “screening” section doesn’t belong here. The section explained in dot points is not referenced at all. The image is great, but there is no references to the original image or any explanation of the image itself. Genetic counselling subheading also doesn’t belong in this section.

*Etiology: Clear and easy to follow but there are words that need defining in the glossary. The section would benefit if the image of the chromosome was moved here. Perhaps more explanation on the FMR gene. The first image could do with a bit more explanation. There are words in there eg: 5UTR that are not easy to understand.

*Development of disease: Good, the subheadings help and its well-formatted. Need a picture explaining the development.

*Signs and symptoms: The image is great, you can use this as your introduction to make it a bit more engaging. You should also make it bigger and explain the distinguishing features. The research is thorough!

*Diagnosis: Very short, needs more detail.

*Treatment: Love the colour, very detailed

*Glossary: Needs a lot more work! There are many words that you will need to define. For example “ allele, permutation, asymptomatic...” list goes on.

*Reference: What’s happening in references 3-8? That’s not proper referencing format. Number 41 reference – a link isn’t a reference.

*Overall: You keep referring to the disease as either fragile X syndrome or FXS. It’s best to stick to one or the other to avoid confusion. Need more interesting images. Some excellent research but it could do with a bit of work. Good job so far.

--[[User:Z3290270|z3290270]] 02:31, 29 September 2011 (EST)

'''Group 5'''

Introduction: Good pictures but they need to be bigger. Also, this section seems like a brief summary of the sections to come. I think it would be good if you included some more general background information on fragile x.

History: This section could be longer. The table would look good with some pictures in it.

Epidemiology: Great section and I like the diagram but some of the words in the diagram are hard to read.

Genetics: This section is reasonably well explained. The genetic terms need more explaining though.

Development: Good section but needs some pictures.

Signs and symptoms: Great section. Well written, flows well and easy to understand. Needs more pictures though.

Diagnosis: This section seems a bit short. Maybe you could explain how the diagnostic techniques work.

Treatment: The table seems too text heavy. Maybe add some pictures to break up the text.

Recent research: overall, good section. --[[User:Z3291324|z3291324]] 23:23, 28 September 2011 (EST)

Group 5

Hi, I can see some progress on this page which is good, content is interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: What is FMR1 gene? Need more information here, as in when was it first discovered, some stats
#* Epidemiology: I think screening information is extensive enough to be a section on its own
#* Etiology: no explanation of FMR1 gene so far, what is its normal function? Also, please refer to images used in this section
#* Development of the disease:nice succinct, easy to follow section. Perhaps add an image for one of the stages mentioned here?
#* Signs: REFERENCING!!! But, content is good and interesting
#* Diagnosis: An image here would be nice, and an explanation of how the technology is used to diagnose FXS
#* Treatment: Nice table with good information
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to balance out the text and image ratio, some good subheadings
#Content is correctly cited and referenced.
#* poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* I feel more research needs to be done here
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#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.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* Although the content is here, there is still a lot of work needed to make this page feel complete
* glossary is very lacking in terminology
* need more images
* further research would be nice to explain this disease in more detail

--[[User:Z3291643|z3291643]] 22:56, 28 September 2011 (EST)

'''Group 5:'''

•The introduction lacks referencing and is a little short, but good use of the images to gain the attention of the reader though as I was reading it I would have preferred for the images to both be on the right hand side.

•The student drawn image on the right is not explained very well and does not contain the correct copyright information.

•Is the diagnosis section finished? It seems a little short and lacking in detail, maybe add some more information to this section, perhaps also an image to help build up this heading and make it more balanced with the other sections.

•Glossary is incomplete and should be in alphabetical order

•References are repeated, but good work on the research

•Overall I liked the formatting of the page, it is easy to read visually appealing and a good use of images to balance out the text.

--[[User:Z3332183|z3332183]] 21:28, 28 September 2011 (EST)

'''Group 5'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there and well described.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Future research is well researched, but is there any other research possibilities that are on going to show breath of research? Glossary needs to be expanded - FXS as an acronym needs to be put there. Table in treatment has too much text. Put the text outside the table and use the table to summarise the content. The information in diagnosis is too brief and could go into a table. Consider expanding that section and provide more information on how and why the techniques diagnoses FXS.

'''*Content is correctly cited and referenced.'''
File:Fragile site appearance and distribution.jpg needs to be correctly referenced. Duplication of references need to be fixed. Emotional characteristics, Language and Speech, Physical phenotype and Physical phenotype section needs references.

'''*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.'''
no explanation given for File:Fragile x chromosome..jpg. more images would be good (Eg: in Fetal Development section maybe include an image of what a fetus looks like who has FXS?)

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Decent reference list and good in-text citation but is missing referencing in some areas.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Fetal development detailed.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has followed the guidelines but some changes would be good.

--z3329495 21:17, 28 September 2011 (EST)

'''GROUP 5: Fragile X Syndrome'''
*Info in the intro is ok but could be improved by maybe including more of an explanation of the CGG codon (some may not know what a codon is and what this implicates) and a small sentence on FMR1 gene
*The placement of the two images in the introduction is a bit weird, it disrupts the end of this paragraph. Consider just putting them on the same side or putting one of them in a different section
*I don't think the first sentence of the history section is history related, looks like it could be better placed in the intro
*Timeline is ok but could possibly be researched more to include more dates, but it's good that it goes up to 2010
*I don't know if Screening/Population testing goes under epidemiology, i think it's more part of management/diagnosis
*Etiology info appears clear and concise, maybe the image of the gene would be better placed in this section
*I find the section development of disease informative and summarised well. I like the way it's structured (subheadings are fitting), an image could improve this section
*Signs and symptoms looks like its been researched extensively, info is comprehensive and summarised well, a graph or another image could improve this section and balance out the text
*Physical phenotype has no referencing (where did this info come from?)
*Diagnosis is very underdeveloped, a lot more explanation is needed for these diagnostic techniques, images could also help improve this section
*Treatment is well researched, use of a table here is suitable, however maybe you could break up the writing by splitting up the Treatment Option and Description into two different sections of the table
*Recent Research is ok, a good intro paragraph may improve this section, maybe provide more recent developments

Overall:
*Glossary is incomplete and many words need explaining, consider linking the highlighted words to the glossary as an improvement, also it might be a good idea to include acronyms in the glossary as well
*legends of images could be expanded a little more
*Reference list needs some work, I don't think links to websites are the proper way to reference

--[[User:Z3331556|z3331556]] 21:15, 28 September 2011 (EST)

'''Peer Assessment Group 5-Fragile X Syndrome'''
*The introduction contains a little bit of heavy info in it. You might want to introduce the complex concepts e.g.methylation of the CGG triplet so the reader can ease into the page.
*The absence of references in the introduction makes it feel unreliable.
*The History seems to be succinct, good work.
*Nice diagram in 'Epidemiology', however it is missing a description and copyright information
*Avoid the italics as it makes the page look inconsistent as you dont have italics very often throughout
*'Development of Disease' is divided well into distinct sub headings, easy to follow
*'Signs and Symptoms' is heavy with too much information, can you summarize some of it to condense the whole section. Also maybe consider finding some images to give it a better balance.
*'Diagnosis' requires a little more explanation of what is involved in the different types of methods.
*The table in 'Treatment' needs division of the second column maybe into treatment option and a separate description just to make it look less heavy
*'Recent Research' is structured nicely, makes it a lot easier to read
*The definitions in 'Glossary' are inadequate
*Avoid italics in the glossary
*The reference list needs some major reformatting
--[[User:Z3308968|Tahmina Lata]] 19:43, 28 September 2011 (EST)

'''Group 5: Peer Assessment'''
* Your page looks a bid 80's with all the different pinks in your table. Not a bad thing, however may be just one colour per table would be enough
* The introduction is too brief and written a little careless and lacks referencing.
* The history table is good in the way that it's chronologic and easy to read but you could write a bid more about the relevance of these events.
* Your drawing needs some copyright information and if the writing would have more contrast it would come more into account.
* The aetiology section is informative overall but some long sentences could be separated and more explanatory. Put the pictures on the same side may be to give it a bid more shape.
* The development of the disease section and signs and symptoms section read well and there is good use of subheadings.
* Is there some current research you could talk about?
* Your glossary and your references clearly need some editing and fixing up
* Overall your page seems to be written a bid careless but there are bids of interesting information in there. --z3279511 17:10, 28 September 2011 (EST)

'''Peer Assessment #5'''
*Intro looks funny with a pic on each side of the text – reconsider this formatting. Maybe both on one side and one under the other?
*Intro 1st para is very detailed for an intro- perhaps explain it more, or in more general terms. The detail will come later
*The intro sentence in history would be better in the intro.
*You keep referring to the FMR1 gene, but I have no idea what this is or how it is relevant. Please explain it somewhere! Maybe have a short para just on it and explain about it.
*In signs and symptoms, are ‘emotional characteristics’ and ‘language and speech’ meant to be their own subheadings, or subheadings of ‘intellectual development’?
*Diagnosis section is not complete, needs a lot more info and explanation of the techniques, how they work, why they are used/relevant. – Modified PCR section is too wordy.
*Treatment table is good, can you stretch it so it takes up the whole box instead of being centered? Would look better
*Recent research – surely there is more you can discuss/other areas?
*I’m sure everyone else has mentioned it, but the glossary needs work. Really, just define lots of the ‘big’ words, as you can’t assume everyone knows what they all mean.
--[[User:Z3332824|z3332824]] 11:59, 28 September 2011 (EST)

''' Group 5 Peer Assessment'''
* First student figure has no explanation as to what it's all about, and is a pretty simple diagram. What does it contain? Where is your copyright information? The same can be said with the second student-drawn figure. Make sure this is fixed!
* The introduction section appears to be pretty short. Try to keep away from using the brackets and just enter your information in a continuous format.
* The headings and subheadings work quite well. However, the lack of images in the signs and symptoms section make this difficult to read; it seems like a large block of text without anything to assist in the breakup of the page (making it difficult to read and easy for us to lose attention).
* Subheadings are used quite well. The treatment section is well presented in table format, but once again, any images to help break things up?
* The recent and future research section doesn't seem to be completed. Is there anything that can be done for the future of the disease? Is it related to any other disease processes? The glossary also seems short and isn't in alphabetic order. Please add all the terms to the glossary to ensure that there is completeness of the project! There are many terms that are difficult to understand, so slot them in here.
* There just needs to be more work done overall to ensure that the project flows smoothly and all the smaller details are accounted for. At the moment there is still a large part of the project that feels quite sketchy and requires more work.
--[[User:Z3288827|Leonard Tiong]] 10:33, 28 September 2011 (EST)

Group 5: Fragile X
*Introduction: Maybe a bit too concise, some of the content that should be in the intro is missing. Maybe this should be redone with references! Also, it doesn’t draw the reader’s attention unfortunately.
*History: Simple table, but a small explanation regarding the significance of the discoveries would be very helpful.
*Epidemiology: Nice picture, had to tilt my head a little. The “Screening/Population testing” seems like a whole new section itself. Might have to look into that?
*Etiology: This section was very well managed.
*Development: I like the subheadings, maybe an image to help add some visuals, but not required.
*Signs and Symptoms: This again, was well done, though detailed, the mass text was slightly disorientating, another image perhaps?
*Diagnosis: Looks incomplete, more info required, probably another sub-heading would do.
*Treatment: Best section in this webpage. Detailed and neatly laid out.
*Glossary: Some explanations and a few more words added here would do the trick!
*Overall: The basic fundamentals are there, some more info here, and a few tweaks there is all that is needed! Keep it up.
--[[User:Z3332327|Lisa Xiao]] 01:25, 28 September 2011 (EST)

'''Group 5'''

*Introduction should be explained a little better and also referenced
*Hand drawn image needs the correct referencing/copyright info
*Good use of subheadings in epidemiology
*Etiology is a little hard to follow
*Development of disease needs an image to break up the text
*Signs and symptoms is very text heavy- try to change it up a bit i.e. use of dot points
*Good use of table in treatment
*Glossary needs to be extended
*Overall, this has potential to be a good project with a few adjustments

'''Group 5'''

*Introduction: too much detail, give an overview. Only one of the images would be enough.

*History: well done

*Epidemiology: screening / population testing should be a separate section, very good image

*Etiology: well done,

*Development and Symptoms: both sections are clear and easy to follow, good use of subheadings

*Diagnosis: seems incomplete

*Treatment: very detailed

*Research: I would add some other examples. If you want to outline only autism, maybe change the heading.

*Glossary: there is a lot missing

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 21:31, 27 September 2011 (EST)

'''Group Peer assessment'''
*Introduction images placement may work better on one side or below the information though current placement is confusing affecting text as well.
*History requires more elaboration as well at least indication of the founder in the introduction of the history even an image of the founder would benefit this section, although the timeline is nicely done.
*Development and disease would be better as a sub heading under eitology as development of the disease links with the causation of the disease.
*Glossary needs work done as most terms are genetic related and those without a genetic background will find difficulty understanding the web page.
*Referencing only needs to adjust the links, links need to be sited properly manually.
z3332250 23:50, 26 September 2011 (EST)

Group 5 Peer Review

*Introduction does not entice the reader to read the rest of the page. Maybe less scientific language in the introduction?
*Table under history is well presented and visually appealing
*“Postnatally” and “postpubescent” need to have “development” added to the subheadings
*Well referenced
*The consistent colour scheme throughout is a nice touch
*Another image under signs and symptoms would make this section look more balanced
*Diagnosis seems brief-add information or perhaps merge with another subheading
*Glossary needs to be expanded
*Logical, clear and organised structure
*Overall, a good page. The bulk of it is there. If each section just changed some minor things, this page would improve greatly.
--[[User:Z3308965|Fleur McGregor]] 19:38, 26 September 2011 (EST)

'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it could be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

--Z3389806 07:34, 26 September 2011 (EST)

'''Group 5 Critique'''

#• Introduction should not contain clinical manifestations. It should introduce the topic as a whole. This section needs to be re-written
#• The history section is ok. The timeline could be explained a little better to give a clearer view of what the history of the disease is to the reader
#• Epidemiology should not contain the advantages and disadvantages of population testing. This should be another section in itself
#• Aetiology was fine
#• Development of the disease was ok
#• Signs and Symptoms was good
#• Diagnosis needs to be more detailed than what it is
#• Treatment and recent research is impressive
#• Glossary needs more terms added to it. It is too short, however that will be fixed when you add more explanations to the other sections and define the terms here.

--[[User:Z3289991|Robert Klein]] 18:57, 24 September 2011 (EST)

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

* I liked your page as it had a simple and easy-to-follow lay out
* Some of the images could have been made larger on your actual page just so that it adds dynamics to your page
* I was left wanting to know more about the diagnosis, this section was quite brief
* I personally found your treatment table hard to read because there was so much information. Personally I believe that maybe dot-point form could have been used to get your main points across.
* Perhaps expand upon your glossary as there were some words that weren’t in there that maybe should have been.
--[[User:Z3332629|z3332629]] 15:25, 22 September 2011 (EST)

'''Group 5 Assessment'''
*The Fragile X Chromosme. Jpg needs both an explanation and referencing.
*There is no referencing in the Introduction section. Where did you get this information from?
*History- Good idea to setup using a chart to organize the data. First time I’ve seen that.
*Fragile X Inheritance jpg looks great!!! Way to incorporate the data into a figure. However, it does still need citing.
*Not all the information in the Screening/Test Population is cited. Where is this information referenced from?
*The Development of Disease portion could use a figure or two to make it more appeasing to look at.
*Some of the information under Signs and Symptoms is also not cited. Where was this information drawn from?
*Good chart under the treatment section. However, maybe try a bullet list on the right hand column to help set the ideas apart from each other?
*The glossary link seems a little short… Are you sure there aren’t any more words which would be helpful to define for the audience?
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
*Overall, good work! Just work on the referencing and some of the visual aspects.
--[[User:Z3391078|Z3391078]] 15:09, 27 September 2011 (EST)

Group 5
* Straight into it hey- a little bit more of an “introduction” might help sorry. The first line kind of scared me. Yes it is relevant information but I think you need to almost ‘warm the reader up’ if you know what I mean. When reading anything I don’t think jumping straight into the nuts and bolts of how it works benefits anyone. I think you should start with what it is and why it is important that the reader learns about your topic
* The history section is brief and I don’t actually understand the relevance of the discoveries. While putting the information in a table shows that you know how to format it to look pretty, it is not the most effective way of showing
* Your hand drawn images still need to be referenced and copyright put on them
* Reading through I am overwhelmed by the content. This may be due to a lack of proper introduction or early explanation. I feel like the information isn’t as accessible as it could be
* Development of the disease would work well in a table I think
* Maybe put the clinical manifestations into dot points? I just feel like everything is a bulk of text and it would be better if you broke it up a little
* An image in diagnosis would help
* Treatment works well in a table
* Glossary could be extended
* You are on the right tract it is just a very heavy project. The content is all there but I found it really hard to get through.

'''Group 5'''
* Great structure with headings and subheadings, very easy to follow and read.
* Nice succinct intro. good over view of the disease. - Maybe you could dot point phenotypic abnormalities
* Some areas a little text heavy, additional pictures would fix this problem. for example some more pictures in signs and symptoms.
* Good simple history, well researched. easy to follow.
* Maybe Screening/Population testing could be its own heading.
* Great section on development of disease! I like the format very interesting relevant information! well done!
* Treatment section well put together but a little text heavy- try condensing info or bullet points.
* Make sure all the pictures are referenced properly.
* Nice to see your references grouped.
* NIce student drawn picture.
* Make sure all your acronyms/ scientific lingo is in the glossary.
* I liked that you has a continuous colour scheme for your tables. It makes your page look very neat.
* The bottom of the page is a little text heavy.

*'''Introduction''': Concise and to the point.
*'''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.
*'''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.
*'''Screening/Population testing''': Looks fine.
*'''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.
*'''Development''': Well explained, good use of subheadings.
*'''Signs and Symptoms''': Also well explained, good use of subheadings.
*'''Diagnosis''': Too short. What about non-genetic diagnosis?
*'''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?
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?
*'''Glossary''': Too short, more terms need to be explained.
*'''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.
*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?

'''Group Project 5'''

*The introduction was too in detail and did not seem like an introduction. Also there are no references ?
*the history is easy to read
*Etiology - very nice section of information
*Development of the Disease - was a good idea to put this in and the information is easy to read, maybe include some hyperlinks to the glossary?
*The treatment table is quite informative and easy to read due to its structure and quite appealing to the eyes
*More should be added to the glossary

--[[User:Z3330313|z3330313]] 20:02, 28 September 2011 (EST)

'''Peer Assessment: Group Project 5'''
*The introduction has no references.
*More pictures in the sections on development, signs and symptoms and diagnosis would help to make the written work easier to follow. Examples of pictures that could be added are images of neural crest development put in the development section or images of diagnostic techniques in the section on diagnosis.
*The section on treatment is clear and informative.
*The different diagnostic procedures could be explained more, such as how they are each conducted.
*Instead of having the uncommon words highlighted in bold, maybe you could link the words to their definition down in the glossary section.
*Some of the references are duplicated. They can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
*In conclusion, this project is both accessible to people who have no great scientific knowledge, but also delves into quite specific knowledge. A good balance.
--[[User:Z3217345|z3217345]] 21:59, 27 September 2011 (EST)

'''Peer Review'''

* the layout was not well structured
* was able to understand the disorder

--[[User:Z3060621|z3060621]] 21:31, 28 September 2011 (EST)

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{{2011GroupDiscussionMH}}

=='''Discussion'''==

Hey,
I'm under the impression that he is closing it tomorrow at 5pm.
Also, make sure you aren't editing stuff out. (Tara, im looking at you :P you edited out some of my stuff, but it's all good).
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

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'''BORIS!'''
This is what you missed in todays lab: you need to read through the peer review comments and work on the comments that are applicable to your section (although you don't have to agree with all the comments), it is also now time to work on all the sections together and we still need more pictures (make sure they are referenced properly and include the student template - if we have any material not cited properly, Mark is going to delete it), we also need to look into maybe adding videos to our page and Sandra would like us all to contribute to the recent research section. We have 2 weeks to finalise our wiki and our page will be closed at 11am two Thursdays from now. Thanks!

--[[User:Z3290815|Tara Lofthouse]] 19:13, 29 September 2011 (EST)

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Collins SC, Coffee B, Benke PJ, Berry-Kravis E, Gilbert F, et al. (2010) Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype. PLoS ONE 5(3): e9476. doi:10.1371/journal.pone.0009476

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Nice work Sandra! I will keep looking and i see you changed your table to pink too haha --[[User:Z3290815|Tara Lofthouse]] 20:54, 18 September 2011 (EST)

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Hey guys, i have just edited our group page and put up 3 pictures! Please try to find more before Monday (especially under development of the disease and signs and symptoms as these parts are so dense with writing and thus need pictures to break it up a little bit)! Cheers, --[[User:Z3290808|Sandra Issa]] 00:24, 18 September 2011 (EST)

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Here:

http://3.bp.blogspot.com/-88xXtruHpyo/TlaALBe6CaI/AAAAAAAABx8/ZMdZULFKEns/s1600/happy%2Bcamper.jpg

{|
|-
| Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)
| 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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.
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.
Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients). Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.”
|-
| Treatment of Mood Instability and Aggression
| 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.
Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”
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.”

|}

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Hey guys, yep i will be there at 10 count me in! --[[User:Z3290808|z3290808]] 09:42, 15 September 2011 (EST)

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It looks like it is going to be late nights all round. We should try and pump out an intro in that time tomorrow as well as at least one image? --[[User:Z3290815|Tara Lofthouse]] 18:52, 14 September 2011 (EST)

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Okay, Tomorrow at 10am it is. I'll finish my stuff off tonight (it looks like being a late night :P).
I'm assuming that it doesn't have to be perfect by tomorrow. It just needs to look alright, so that people can give us feedback before we finish it, yeah?
Also, Boris, Interview is on the 27th. I was just visiting a friend. I'll tell you how it goes though, when it does happen. --[[User:Z3290618|Ziggy Harrison-Tikisci]] 17:43, 14 September 2011 (EST)
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I can make it at 10am on Thursday as well --[[User:Z3290815|Tara Lofthouse]] 12:08, 14 September 2011 (EST)

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Ooo, interview? How'd it go?
I don't have time to meet up today (Wednesday), but I can see you guys in the lab at 10 tomorrow, before the class.
--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)

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Hey Guys, Sorry I've been in Melbourne for the week, so haven't done any work. Getting on it now. Going to do all my referencing, editing etc.
Wanted to ask if there is a time when we can get together, go through it all and make it pretty. Did we just want to do this before our lab on thursday, or if you guys have some time on wednesday afternoon?
Furthermore, how harsh is the criticism/feedback? Doesn't mince his words, does he? --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:51, 12 September 2011 (EST)

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Hey Boris yes i am experiencing the same problem. I cannot see the references and the reference list looks like a bunch of arrows facing superiorly. I got a bit worried but then checked the other groups and they had the same issue. I'm not sure what we can do? Let me know. ---[[User:Z3290808|Sandra Issa]] 09:49, 9 September 2011 (EST)

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WHAT HAPPENED TO OUR REFERENCES. Can you guys do me a favour and tell me if you can see them? I was trying to put in an image just then and when I did the save it came up with references wiped. I tried undoing my last edit to no avail. There are still 30 something references, there's just nothing IN them. When I finished my word edit earlier today I actually saved the ENTIRE script as a word document; when I tried to rewrite EVERYTHING with that same (working) script it still came up with stuffed up references.

Let me know if you guys see the same problem. If you do, I'll have to get in contact with Mark Hill to fix the script.
--[[User:Z3290689|Boris Zolotarev]] 23:31, 8 September 2011 (EST)

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I hate how the times shown on the editing thing are totally out of whack....can I post anything up at the moment? ><
--[[User:Z3290689|Boris Zolotarev]] 23:27, 7 September 2011 (EST)

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Hey guys, i have just added the diagnosis part of our page and have also finished the treatment. Let me know if you think the treatment is too long? Or if you want to make any changes to the "Recent Research" part of our page.

Also, i will add in more references for this part very soon. I have put in a general reference (review article) but will make sure i include all references used very soon.

Have a good night, --[[User:Z3290808|Sandra Issa]] 21:16, 7 September 2011 (EST)

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Suggestion: rename '''Development of disease''' to '''Progression of disease'''. Also, I should have a heap up later tonight, I'm compiling it all in a separate document at the moment.

--[[User:Z3290689|Boris Zolotarev]] 15:39, 7 September 2011 (EST)

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Hey guys, just letting you know that i have found a great article which addresses many current 'treatments' for FXS. Also, i have found another article which summarises the current methods of diagnosing FXS. I will add this information (what i think is most relevant from the articles) onto our group page under the headings "treatment" and "diagnosis" '''very soon'''. Please feel free to add in anything that you believe i have not addressed under these headings. Also, i will try to edit our page as a whole soon so that it looks more uniform in appearance. Over the next couple of days we should all read each of the sections and try to add in additional information that someone else may have missed. Also, a reminder to keep an eye out for relevant pictures that have unrestricted access to add onto our page!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:32, 5 September 2011 (EST)

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Hey, I'm doing a whole bunch now. I'll properly reference it all later, but I'm getting a lot of it off the american National Institute of Health. They've got references for all of it. So when I have more time, I'll go through those references, add them, and edit the information. So, what I put on the group page will just be an overview. Also, you people should go to bed earlier :)
http://www.nichd.nih.gov/publications/pubs/fragileX/sub6.cfm
--[[User:Z3290618|z3290618]] 09:49, 1 September 2011 (EST)

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z3290808: I don't know why it wouldn't let you save, i wasn't editing at that time. Try again and if it doesn't work maybe paste your work here with your references and one of us can put it onto the project page for you?

Boris: At least something is up :) My section needs a lot more editing and a lot more cross checking with other references as well.. Any progress is good progress at the moment
--[[User:Z3290815|Tara Lofthouse]] 03:35, 1 September 2011 (EST)

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Heya, I took a stab at my section but I'm a bit dead at the moment '''(points to timestamp)'''. I'll try get some more done tomorrow between the lecture and lab.

On the plus side, I added another 6 or 7 references to our thingy ^^

--[[User:Z3290689|Boris Zolotarev]] 01:28, 1 September 2011 (EST)

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Guys it's not letting me save what i have written onto the group page! Is anyone currently on and trying to edit at this same time?
--[[User:Z3290808|z3290808]] 22:41, 31 August 2011 (EST)

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Yo Boris, You do Etiology, I'll do signs and symptoms. We can work towards the middle.
That leaves history and epidemiology to Tara and Recent research to Sandra. And then we can all refine it/make an intro.
We can at least do that to start with.
Also: can everyone contribute to the glossary. If you find any terms that people (eg. me) wont understand, please keep them.--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:10, 25 August 2011 (EST)

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The only reason why we need to put our names down now is to satisfy the weekly individual assessment but of course we can change things. Just put your name down for epidemiology or whatever was left over and we'll discuss it tomorrow. Maybe if we could get to the lab 10-15min earlier because we never get enough time at the end of the lab?

--[[User:Z3290815|Tara Lofthouse]] 19:50, 24 August 2011 (EST)

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Just skimmed through this (damn I left it late >< ), should I nominate something now or should we discuss it tomorrow?
Also, what do you guys think of having some sort of realtime chat method? Facebook or something of the sort...
--[[User:Z3290689|Boris Zolotarev]] 19:17, 24 August 2011 (EST)

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Yeah i know but the ones i put my name down for are really not that lengthy. We definitely need to have a chat tomorrow.
--[[User:Z3290815|Tara Lofthouse]] 17:45, 24 August 2011 (EST)

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Hey guys, you haven't left much for Boris and i to do lol .. I don't mind doing the recent research part - focussing on autism and fragile x.. but then i don't know what Boris would do? I will sign my name for now but i think we will have to change it around a little to better make the work load equally spread.

Cheers, --[[User:Z3290808|Sandra Issa]] 16:17, 24 August 2011 (EST)

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I've taken it all on board and changed it. I'm fine for you to do whatever you want but doing both the genetic component and the signs and symptoms might be a lot of work. As long as everything is spread evenly i don't mind :)

--[[User:Z3290815|Tara Lofthouse]] 16:35, 23 August 2011 (EST)

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Hey, I was wondering if anyone minds if I do 'Genetic contribution'. Also, is it okay if I follow the timeline of the disease? I will start with the chromosome, saying what the defect causes at a molecular level, and then when it first presents, and how it affects the development etc up until how it presents in the adult. Which means I'd probably do "Signs and symptoms (clinical Presentation)" as well.
ALSO, we need to do a brief history of the disorder. So, below I've just tweaked the layout Tara and Sandra put up: let me know what you think

* Introduction
* History of Disease
* Epidemiology
* Etiology
** Genetic contribution
* Development of Disease
** Fetal Development
** At birth
** In Adult
*** Signs and symptoms
* Recent research
** Fragile X and Autism
** Diagnosis
** Treatment
--[[User:Z3290618|z3290618]] 15:18, 23 August 2011 (EST)

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Yeah, i think it makes sense how you've got it Sandra. However like Boris said maybe instead of having the heading "Autism and Fragile X Syndrome" maybe we could have recent research/current studies or something along those lines and include it there along with diagnosis and treatment? Do you think that etiology is too similar to genetic contribution?

ALSO!!!
What headings would you like to research? I set up a "Who's doing what?" heading on this page to sign your name next to.

--[[User:Z3290815|Tara Lofthouse]] 12:39, 23 August 2011 (EST)

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Hey guys, i have come up with a couple of headings that we can use:

* Introduction (short summary)
* Epidemiology
* Signs and Symptoms (Clinical Presentation)
* Etiology
* Genetic Contribution
* Autism and Fragile X syndrome
* Diagnosis?
* Treatment?
* References

Tara i also like the format that you have included below.. i basically have made something similar but in different order based on what i think should come first perhaps? The ones with a question mark beside them are ones that i am unsure if we should include or not. Let me know what you think!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:03, 23 August 2011 (EST)

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Hahaha of course it's your place to say so.. good suggestion, i'll fix it up now and if we want to change it again than that's no problem. I just thought i'd put something up to get started and we can go from there. What i've done is no where near completed.
--[[User:Z3290815|Tara Lofthouse]] 18:52, 22 August 2011 (EST)

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(I know it's not my place to say so before I've submitted my own suggestion but) I think I'd put "Autism and Fragile X Syndrome" within the "recent research" subtopic. I'll put up a suggestion by tomorrow evening, if not earlier.
--[[User:Z3290689|Boris Zolotarev]] 09:27, 22 August 2011 (EST)

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'''Hello everyone,''' what do you think about using the following headings for our project? Are there ones that you think we could omit or ones that you would like to add? We also need to decide on who is doing what.
* Signs and symptoms
* Diagnosis
* Genetics
* Etiology
* Epidemiology
* Treatment
* Recent research
** Autism and Fragile X Syndrome
* References

--[[User:Z3290815|Tara Lofthouse]] 16:26, 21 August 2011 (EST)

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[http://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Lab_2_-_Group_Project Group project] --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:58, 4 August 2011 (EST)

[http://www.ncbi.nlm.nih.gov/omim OMIM]--[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:59, 4 August 2011 (EST)

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Here's another interesting topic.

[http://en.wikipedia.org/wiki/Apert_syndrome Apert Syndrome aka acrocephalosyndactyly] --[[User:Z3290689|z3290689]] 11:38, 11 August 2011 (EST)

=='''Congenital Hypomyelinating Neuropathy'''==

What do you guys think you of this topic [http://omim.org/entry/605253 Congenital Hypomyelinating Neuropathy]?

There are quite a few articles on it:

Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination.

Analysis of congenital hypomyelinating Egr2 Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination.

P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves.

Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg–Hirschsprung disease: Phenotypes linked by SOX10 mutation.

A lot of them overlap with their findings and the focus of their studies, so it seems to be a pretty thorough topic.

--[[User:Z3290689|Boris Zolotarev]] 21:03, 7 August 2011 (EST)

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I’m all for doing '''Congenital Hypomyelinating Neuropathy''' as our topic.

Here are some articles I have found:

'''Research Articles:'''

[http://neuro.cjb.net/content/29/8/2312.full.pdf+html Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure in Mice Carrying the Egr2 I268N Mutation]

* 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

[http://jnnp.bmj.com/content/48/12/1269.full.pdf Congenital hypomyelinating neuropathy]

* 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:'''

[http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TBD-3W37BMX-C-1&_cdi=5140&_user=1975841&_pii=S0887899498001386&_origin=&_coverDate=03%2F31%2F1999&_sk=999799996&view=c&wchp=dGLzVzb-zSkWA&md5=d2e9e64dfc821d71ec81675f01932b8a&ie=/sdarticle.pdf Congenital hypomyelinating neuropathy: two patients with long-term follow-up]

* 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

--[[User:Z3290815|Tara Lofthouse]] 12:22, 9 August 2011 (EST)

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=='''Fragile X Syndrome'''==

==='''Articles'''===

Hey guys,
I had a look at Congenital Hypomyelinating Neuropathy and to be honest i did not find it very appealing. I found the disorder "Fragile X Syndrome" to be very interesting! Can you guys please check out the following link on [http://www.fragilex.org/html/cause.htm/ Fragile X Syndrome] and let me know if the disease also interests you!? I found the information on it is quite extensive and the disease is well known. If you do not want to base our project on this syndrome, i am sure we can decide on one we can all enjoy studying! :)

Here are some interesting articles that i have found on '''Fragile X Syndrome''':

* '''Review Article''': Fragile X syndrome: from gene discovery to therapy <ref><pubmed>21196228</pubmed></ref>

- This review focuses on the molecular and biochemical pathways shown to be relevant in the Fragile X Syndrome. It describes that a mutation in the FMR-1 gene was found to lead to Fragile X Syndrome due to excessive repeats of the trinucleotide sequence CGG which is known to inactivate the FMR-1 gene, making the X chromosome fragile and prone to breakage. This review article also demonstrates the many vital functions of the FMR-1 gene such as its role in RNA transport and stability, thus absence of the protein transcribed and translated from this gene is thought to affect brain development and thus leads to signs of mental retardation.

* '''Research Article:''' DNA methylation represses FMR-1 transcription in fragile X syndrome <ref><pubmed>1301913</pubmed></ref>

- This research article explores the two molecular differences of the FMR-1 gene in normal individuals vs. those with Fragile X Syndrome. These differences are an increase in size of an FMR-1 exon containing a CGG repeat and abnormal methylation of a CpG island 250 bp proximal to this repeat. This research article also shows how these two abnormalities repress transcription of the FMR-1 gene, leading to the absence of the FMR-1 protein which is thought to be the contributing factor to the Fragile X phenotype.

--[[User:Z3290808|Sandra Issa]] 19:53, 9 August 2011 (EST)

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Here are some articles I have found for '''Fragile X syndrome''':

'''Research Article:''' The state of synapses in Fragile X Syndrome <ref><pubmed>19325170</pubmed></ref>

* Fragile X Syndrome is the most common inherited form of mental retardation and a leading genetic cause of autism.

* Evidence that suggests alterations in synapse number, structure and function are associated and contribute to both Fragile X Sydrome and autism.

* Fraile X Syndrome is caused by loss of function of the Fmr1 gene which encodes the RNA binding protein, FMRP (FMRP is present at synapses where it associates with mRNA and polyribosomes).

* FMRP is also has a role in synapse development, elimination and plasticity.

* An understanding of the molecular and synaptic function of FMRP, as well as the consequences of its loss, has led to the early developments of therapeutic strategies for Fragile X Syndrome.

'''Research Article:''' Fragile x syndrome: history, diagnosis, and treatment. <ref><pubmed>6348096</pubmed></ref>

'''Review Article:''' Systematic review of pharmacological treatments in fragile X syndrome <ref><pubmed>19822023</pubmed></ref>

'''Review Article:''' FMR1 and the fragile X syndrome: human genome epidemiology review <ref><pubmed>11545690</pubmed></ref>

--[[User:Z3290815|Tara Lofthouse]] 14:37, 16 August 2011 (EST)

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==='''Images'''===

[[File:FMR4 is silenced in fragile X syndrome.jpg|thumb|FMR4 is silenced in fragile X syndrome]]

[[File:FMR4 is silenced in fragile X syndrome.jpg|350px]]

File:FMR4 is silenced in fragile X syndrome

--[[User:Z3290808|Sandra Issa]] 10:20, 14 August 2011 (EST)

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[[File:Hippocampal_Formation.jpg‎|thumb|Hippocampal_Formation]]

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

File: Hippocampal_Formation

--[[User:Z3290815|Tara Lofthouse]] 13:49, 17 August 2011 (EST)

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Like?
[[File:Fragile site appearance and distribution.png|300px]]
File: Fragile site appearance and distribution
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 08:55, 18 August 2011 (EST)

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[[File:Journal.pone.0013559.g001.png‎|thumb|FXR1 (A) and FXR2 (B) crystal structures]]

[[File:Journal.pone.0013559.g001.png‎|300px]]

File: FXR1 and FXR2 crystal structures

--[[User:Z3290689|Boris Zolotarev]] 11:00, 18 August 2011 (EST)

== '''Who's doing what?''' ==

* Introduction = DO AT THE END!!!!
* History of Disease = Tara
* Epidemiology = Tara
* Etiology = Boris
** Genetic contribution<ref>http://www.fragilex.org/html/premutation.htm</ref><ref><pubmed>10208170</pubmed></ref><ref><pubmed>11445641</pubmed></ref><ref><pubmed>12638084</pubmed></ref><ref>http://ghr.nlm.nih.gov/condition/fragile-x-syndrome</ref><ref><pubmed>8348153</pubmed></ref>
** Development of Disease
*** Fetal Development
*** At birth
*** In Adult
* Signs and symptoms = Ziggy
** Physical phenotype
** Social interaction
**Intellectual development
* Recent research = Sandra
** Fragile X and Autism
** Diagnosis
** Treatment
* References

==ZIGGY'S STUFF==
Just leaving this here for the next hour, so that I don't have to retype it all (can't get wifi in the embryo lab).

The hallmark of the fragile X syndrome is mental retardation, which was noted as early as 1943 in a report of a large family with 11 mentally retarded males and two mildly retarded females. 64 The clinical phenotype associated with the syndrome has since been widened to include a variety of cognitive, physical, and behavioral characteristics (reviewed in Mazzocco). 65 Almost all males with the full mutation exhibit some clinical features of the fragile X syndrome. Also, most affected males do not reproduce, presumably due to the severity of mental retardation. With regard to cognitive function, affected males often exhibit developmental delay very early in childhood. By the age of 3 years, most males will test in the mentally retarded range. 66 Ultimately, almost all males with the fragile X syndrome are mentally retarded, with severity ranging from profound (IQ <20) to mild mental retardation (IQ 50–70), with most being moderately retarded (IQ 40–54) (reviewed in Hagerman). 67 Physically, adult males often have a long narrow face, prominent ears, a prominent jaw, and macroorchidism (reviewed in Hagerman). 67 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, and mitral valve prolapse (reviewed in Warren and Sherman). 8 Males with the fragile X syndrome also tend to exhibit behavioral features such as hyperactivity, social anxiety, perseverative speech and language, tactile defensiveness, stereotypies (e.g., hand-flapping), and hand biting (reviewed in Hagerman). 67 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. 68 The association of fragile X with autism, however, is not clear because the proportion of males with the fragile X syndrome meeting the diagnostic criteria for autism seems to diminish with age. 68

Physical phenotype
Before puberty, children with Fragile-X tend to have no discernable 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. 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 macro-orchidism: enlargement of the testicles. Fragile-X patients may also have loose connective-tissues, allowing their joints to be more flexible that normal. This may cause complications arising from increased risk of 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.

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. Their anxiety often manifests itself as discontinuous speech and a lack of eye contact.

Results indicate that compared to the control group, individuals with FXS exhibited decreased activation of prefrontal regions associated with complex social cognition, including the medial and superior frontal cortex, during successful face encoding. Further, the FXS and control groups showed significantly different relationships between measures of social anxiety (including gaze-fixation) and brain activity during face encoding. These data indicate that social anxiety in FXS may be related to the inability to successfully recruit higher level social cognition regions during the initial phases of memory formation.
Reference: Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome.

Intellectual development
As a generalisation, the majority of Fragile-X patients have an IQ between 1 and 2 standard deviations below the population mean. This equates to around 40-85. Few Patients lie out-side this range, with approximately 20% within the ‘normal’ range (85-115) and less below 40. Females however, show lower impairment, with only one-third having IQs within the ‘mental retardation’ range.
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.
Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points.

Studies of intellectual function in FXS often demonstrate a mean IQ decline of 4 to 9 standardized points over intervals ranging from several months to 13 years.
Reference: Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Working Memory
First, when individuals affected by the premutation are examined as a group, they exhibit a weakness only for tasks that reflect functioning of the central executive subcomponent of working memory.

Second, when both permutation sub-groups are examined together, the extent of the central executive deficit is significantly correlated with larger CGG repeat expansions.

For permutation males who are asymptomatic, mild executive dysregulation, inhibitory deficits that worsen with age, and declarative verbal learning and memory are notable.

The detection of a deficit in the central executive component of working memory in the fourth decade of life that progressively deteriorates with age suggests a cumulative process that may be a cognitive correlate to the underlying degenerative process identified in premutation males.

The significant correlation between CGG repeat length and central executive working memory in asymptomatic carrier males suggests greater neuropathology in carrier males with larger expansions in FMR1 mRNA transcripts.
Reference: Lifespan changes in working memory in fragile X premutation males

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.

== '''References''' ==
<references/>

2011 Group Project 5

2011-10-12T08:50:05Z

Z3290618: /* Related Links */

{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]

=== 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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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 premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* [http://embryology.med.unsw.edu.au/Defect/fragilex.htm UNSW Embryology: Abnormal Development - Fragile X]

* [http://embryology.med.unsw.edu.au/Notes/neuron2.htm UNSW Embryology: Neural System - Abnormal Development]

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism]

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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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2011 Group Project 5

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= 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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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:Symptoms of Fragile X Syndrome.JPG|thumb|350px|left|Symptoms of Fragile X Syndrome]]

=== 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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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 premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* http://embryology.med.unsw.edu.au/Defect/fragilex.htm

* http://embryology.med.unsw.edu.au/Notes/neuron2.htm

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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/>

----

{{2011Projects}}

2011 Group Project 5

2011-10-12T08:34:59Z

Z3290618: /* Related Links */

{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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:Symptoms of Fragile X Syndrome.JPG|thumb|350px| Symptoms of Fragile X Syndrome]]

=== 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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

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

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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 premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* http://embryology.med.unsw.edu.au/Defect/fragilex.htm

* http://embryology.med.unsw.edu.au/Notes/neuron2.htm

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

* [http://www.youtube.com/watch?v=RV3y_n5ZjFQ Lecture: Neurodevelopmental disorders - Fragile x and Autism

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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/>

----

{{2011Projects}}

Talk:2011 Group Project 5

2011-10-12T08:12:30Z

Z3290618:

{{2011GroupDiscussionMH}}

Hey,
Nice picture in signs and symptoms. Does it have the clearance thing?
I'm going to find a photo to put up now.
I'll see if I can fix your problem with the internal links.
Also, if you want to to a signature just type out -- followed by three ~ manually and it'll work.
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

'''IMPORTANT!'''

Hey guys, i tried to do that internal link thing but it wouldn't work for me even though i tried to do it like how Dr. Hill did it.

Anyways i have put up the reference of where i want to link it to under a heading i created called "Related Links" on our group page. Could someone please try to put these two links in the correct internal link format.

Greatly appreciated, z3290808 (the signature stamp isn't working for some odd reason)

I have also added a new image under signs and symptoms which i have obtained from youtube. Let me know what you think. -z3290808 (Sandra Issa)

Just in case you guys couldn't find it!
--[[User:Z3290815|Tara Lofthouse]] 14:31, 11 October 2011 (EST)

===The final stretch!===

* The group projects will be locked after next weeks practical ('''5:00 pm''') for no further changes.
* You are free to make any changes you wish to the existing project page (additions, deletions, formatting etc).
* You should also go through all displayed uploaded files and make sure they conform to the information requirements I specified in today's practical (without the numbering):
# Correct image file name (describes what the image shows, keep it brief and to the point).
# Original legend information and any clarifying description that shows how it relates to your group topic.
# Correct citation format in its own "Reference" sub-sub-heading (if pubmed extension does not format correctly paste the entire text in and add a PMID number link at the end) You can also link to any other location of this citation, but this is not a requirement.
# The copyright information (Don't just paste, make sure it says that you can use then image).
# Finally include the student image template (copy the following in read mode, and paste in your image information in edit mode) <nowiki>{{Template:2011 Student Image}}</nowiki>

* You should complete all your updates ASAP and not leave everything to the last practical class where you will have limited time.
* We have a guest presenter for next week practical and '''I do not want any Group work during her part of the practical'''.
** Remember all edits are logged and time-stamped, I can see who has been editing when they should doing the practical.

===Last Addition to your Project Page===

* Is a new sub-heading entitled "Related Links".
* This sub-section should link to other pages on the embryology website that relate to your topic.
* Format as a bullet list, link first and a brief description (one line) of how it relates to the topic.
* An example is shown below.

==Related Links==

* [[Placodes]] - this page relates to today's practical as the earliest sensory specialisation visible on the embryo surface during week 4.

----

Hey guys, i have added some more recent/ future research into the corresponding heading! I have also added another picture under this heading. The research is very current (2011) which is good. Hope you guys like it :) --[[User:Z3290808|z3290808]] 13:37, 8 October 2011 (EST)

=== Sandra ===

SAAAAAAAAANDRA:

This is what it will look like: [[Week 2|this is how you make a link to a page on this website thingy bla]]

This is what you type in: <nowiki>[[Week 2|this is how you make a link to a page on this website thingy bla]]</nowiki>
* Where you're linking it from "Week 2"
* Description "this is how you...."

--[[User:Z3290689|z3290689]] 12:45, 6 October 2011 (EST)
----

==='''Discussion 2'''===

Hey, I'll be doing quite a few edits today/tonight. I'm putting up all of my references now.
Also, I'm going to be making sure all of our referencing is in the same format. I noticed there are a few that link the website for an article. I'll try to fix them up.
I want to just check with you guys if the following is okay:
I need to put on my student page what my contribution to the group project is. I'm going to put up "signs and symptoms" without the two pictures. The picture I put in the discussion in the first weeks (though someone else put it in the actual page) and finally the formatting for the tables (but in grey-scale as it was originally). Are there any objections for to that?
Let me know if there is anything else, and make sure you aren't accidentally editing out my edits if we're doing work :D
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

Hey guys, i have edited my diagnosis section - i have put it in a table and have found some relevant videos. Also, i will try to find some more recent research. It would be great if everyone can also pitch in to this section anytime you find some recent research that is relevant to our topic but not addressed in one of the subheadings.
To Ziggy - could you please finish off the referencing for your section Signs and Symptoms. Also if possibly, could you please add a photo to the group page. That would be much appreciated.
Cheers, --[[User:Z3290808|z3290808]] 11:59, 6 October 2011 (EST)

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_5_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_5_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

[[2011_Group_Project_5|'''Group 5''']]: [[User:z3290618]] | [[User:z3290689]] | [[User:z3290808]] | [[User:z3290815]]

----

=='''PEER REVIEW COMMENTS'''==

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
--[[User:Z3284061|z3284061]] 11:54, 29 September 2011 (EST)

'''Group 5'''

* The images might be better all on the same side
* An image is needed in Development
* "Signs and Symptoms" is a little text heavy and needs more references
* Diagnosis appears to be incomplete
* Glossary needs to be expanded
* Links to the glossary might be helpful
* Double referencing needs to be fixed
--[[User:Z3292953|z3292953]] 11:08, 29 September 2011 (EST)

Fragile X Syndrome – Group 5

* Introduction is perhaps a little brief. Some points that could be elaborated on are mentioned. Some referencing issues on the images in this section as well as a better explanation as to what these images actually show, why does the fragile x- chromosome look different?
* Screening could be its own heading and epidemiology could use more images.
* Etiology looks great. Good description in one of the images however the other one is not explained at all.
* Development of disease could use with some images, possibly the use of a table here could better summarize the information.
* Diagnosis could use more information aswell as some images.
* Recent research does not really contain much information, and I thought that the direction of future research could be commented on in this section also.
* Glossary needs completing. Some of the referencing web sites should be fixed up.

--[[User:Z3288196|Z3288196]] 10:42, 29 September 2011 (EST)

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
z3284061

Group 5:

References 5,6,7 & 8 refer to nothing. If all the information for a particular section refers to one reference, you don’t need to link to the same reference after each sentence. Just put it in once at the end of the paragraph, eg under screening/population testing and reference 11.

Good use of pictures especially at the beginning, maybe more in the middle? Also, maybe fix the formatting of the pictures as it disrupts the flow of the page and is distracting. Signs and diagnosis have few pictures making it look like a long trail of writing.

Well done with the glossary so far, but still some terms need to be added as it is incomplete at present.

z3332178 =]

peer review:

*dont like the picture positioning maybe space them out a bit?
*the first portion of history could be removed and just have like the x like description part, also how about a picture of the prson who discovered the disease?
*i think the screening part of epidemiology is irrelevent, it should just be who its affected and how many people suffer from the disease.
*text in aetiology is wquite verbose
*signs and symptoms is way to long, figure out a way to break all the text apart with pictures,tables etc
*little glossary and multiple references present
--[[User:Z3291423|Jasjit Walia]] 10:21, 29 September 2011 (EST)

'''Group 5'''

*intro: put the pictures on one side, will look more appealing and easier to read. Overall good info, easy to read.

*history: the little intro before the timeline is a little awkward and seems unnecessary. Maybe work on fixing this paragraph so it leads into the timeline instead of just talking about chromosomes, I found this abrupt. Timeline good.

*etiology: could be nice to have the images both on one side. It was a little confusing for the reader with the image on both sides.

*development: good section! But isn’t development and etiology the same thing? Maybe not put it as a heading but a subheading with etiology.

*diagnosis: third point FMRP antibody test can be the start of the point instead of writing a presentence to lead into it.

*signs, treatment: both great sections.

*glossary: is a little empty. Might want to include anything scientific like ‘chromosome’ as a normal person off the street might’nt know what that is. Also placing them in alphabetical order is helpful.

--[[User:Z3290558|z3290558]] 09:57, 29 September 2011 (EST)

'''Group 5 peer review'''

Introduction: It is a good overview of the different aspects of this disorder. Increasing the size of the hand drawn image will be good so that the writing can been seen clearly on the main page.

Epidemiology: The image is good and easy to understand. However, perhaps you should position the image next the text which talks about '...females are less likely to show severe signs...'. I think that genetic counseling and screening should be in a seperate management section. It would be ideal if Epidemiology contains more figures, especially if those numbers are in a some table.

Etiology: It would be better is you could explain what you mean by Xq27.3 in the text. I don't quite understand what you mean by '...given the location of the gene on a particularly fragile segment of Xq27.3...'. Although you have explained the figures in the text, it would be better if you add a one sentence summary of what each figure is displaying. This is because people might instinctively look at the figure first and not fully understand it and then read the text. Whereas if they looked at the figure and had some idea what it was showing and then read the text, the etiology of fragile x will be that much easier to understand. I like the size of the image because i can read it clearly.

Diagnosis: Please expand on the mechanisms of each technique. It would also be good to insert an image of each technique so that readers can know what the result of each technique looks like.

--[[User:Z3289301|z3289301]] 09:46, 29 September 2011 (EST)

'''Peer Assessment'''
*Introduction; well written but too brief. Need to include more information.
*Not sure if the 'screening' section is appropriate under the title 'epidemiology' especially because there is no inclusion of epidemiological data gathered from these tests but just explanations about their usage.
*I suggest using Microsoft word, power point or paint to draw the student drawings rather than from hand, especially images such as the one in the introduction showing X chromosome. Would look much more neater and professional.
*It also might be a good idea to hyperlink words in the text with the glossary. Makes it much more user friendly.
*The genetic section is well researched however the information is bit too confusing and the layout is messy. Try using tables to summarize the information.
*The section on 'development' of the gene is well written. Try and include imaged of patients at the different stages to compliment the writing.
*Try and incorporate a table in the 'signs and symptoms' section which is very text heavy.
*Diagnosis: section is a bit too brief. Not sure if this is possible but try and include images of these lab results characteristic of FXS in this section.
*Like the use of table in the 'treatment' section. Much more easier to read and understand.
*Glossary: needs to be expanded.
--[[User:Z3291622|Z3291622]] 09:38, 29 September 2011 (EST)

Be nice?
'''Group 5 evaluation'''

*The information in the introduction is good but it is way too brief. The other section of the page was not introduced or not introduced properly, like the diagnosis section. Adding these bits would probably make the introduction good and a bit more informative as to what to expect from the page. Also reference them.
*The history I think is fine the way it is.
*The epidemiology is good because you have touched upon the demography of the disease and its prevalence. It would have been better if you could add a bit more statistics on the geographical distribution of the disease, as it makes the section more credible than how it already is. Unfortunately I think the section from “Screening… “ onwards is not very relevant for this section. I would consider revising as to where this information should be placed under. I guess this section needs more research overall.
*The etiology is very informative and I think you have gone in-depth in the topic, and is well researched, but I think it needs some revision. The concepts were far too technical and it makes the reader a bit too confused about what the information is actually saying. The images are amazing, and if you could incorporate them in the text it would make the section better.
*The development of the disease section I think should be the pathogenesis of the disease. This section was not done properly, as I was expecting to see how the etiology and all the clinical manifestations relate to each other; instead it was all about the clinical manifestation. I think you need to look further into this section.
*The signs and symptoms section is very informative, but I am questioning the information as it is not referenced at all in most of the paragraph.
*Diagnosis should probably changed to diagnostic tests because the diagnosis is Fragile X. The information is good for introducing the techniques to the reader. I think further description of the tests is needed.
The treatment section has some very good information on it that describes the treatments used for the disease. It could probably be better if you could highlight the actual treatments and make it stand out.
*Recent research is a bit disappointing because the most recent research that were presented is 3 years ago. As a reader, this makes me question the content of the page, whether it is up-to-date or not. It would also be good to have a more recent paper/research and the inclusion of future direction of this disease.
--[[User:Z3290841|z3290841]] 10:24, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*The lone sentence at the beginning of the history is unnecessary.

:*Essay language such as “for example” is a bit out of place on a wiki page. Tailor language to a web page.

:*In the epidemiology section some statements are not referenced. Where are these ‘examples’ coming from?

:*Research section would benefit from the bolding of paper headings or authors names.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:13, 29 September 2011 (EST)

'''Group 5 peer Review'''
* Introduction has good information, but it needs to be more catchy for readers to want to read onto the page.
* the first line of the history section seems not to be so greatly relevant to the history section. Also in the table there’s a 30 year gap at the start of the table. No important things happened during this time?
* I don’t think the information for ‘Screening/Population testing’ is necessary to be put under the epidemiology section, rather under diagnostics.
* Explanation about the genetic location of the mutation should be given. Also information found under aetiology should be re-formatted so it is easier to read.
* The development of disease section has good information. Would it be possibly to accompany these sections with images.
* Some parts under signs and symptoms are not referenced properly as it is lacking the referencing. Also possibly include some more pics/graphs/audio/movies in this section to accompany the text.
*Diagnosis section must be expanded upon. It has potential as concepts are there but more info could be included.
* Nice use of a table in the treatments section
* the paragraph starting with: ‘’ Autism is a disorder whose etiology is not…’’ should be placed to flow with the first sentence in the recent research section. It will make the paragraph flow better.
*acronym for ‘’ Autism Diagnostic Interview (ADI-R)’’ seems bit odd, what does the R stand for?
* if possible add an article from 2011 in the recent research section to make it though you are showing the reader the most cutting edge research in this field.
*Glossary must be expanded upon, many words have not yet been included.
* In the referencing section the referencing is done well. I did notice a repetition in the referencing in reference number 37 and 38. Please fix up.
* More images are needed on the page to get the image and text ration right, especially towards the middle of the page.
*other than that good page people.

--[[User:Z3291317|Z3291317]] 08:44, 29 September 2011 (EST)

Group 5

*Introduction - ok except it was a bit hard to read with the text squeezed between the two images located left and right, maybe both images could be placed on one side, such as the right, to make it easier to read and add to the continuity and flow of the page. There is a lot that could be expanded on to add to the introduction, maybe a brief explanation of the FMR1 gene and the phenotypic manifestations as a result of it being silent.
*Etiology, not really sure but i don’t think you’ve referred to the images included here, formatting could be improved with both images being on one side
*Development of the Disease – very nice heading, information easy to follow and well referenced, best heading on this page, great job.
*Signs and Symptoms – another very well organised section
*Diagnosis – this section could be best suited to a table, making each technique easy to identify and define.
*Treatment – great use of a table, information is very clear and easy to understand.
*Glossary – more terms need to be added, such as the acronyms used throughout the page: ADHD, CGG, PCR, FXS, etc.

--[[User:Z3331469|z3331469]] 07:01, 29 September 2011 (EST)

'''Group 5 Peer Review'''

• Generally good sub-heading structure. The overall flow is consistent (nice pink tables!), however I think it could be tidied up more, for example; images placed on the right hand side of the page.

• Double up’s in references need to be removed.

• Introduction is brief and concise, good!

• Epidemiology could be improved by the addition of a table, and maybe the ‘Screening/Population testing’ section could be a sub-heading on its own.

• The first paragraph in the genetic contribution of Aetiology I feel could be worded better, but nice images and really good description of the cause of the abnormality.

• Development of the disease is a really good explanatory section, really informative! The addition of images here, would really improve it (if able to find them)

• More images needed in the signs and symptoms section. Also maybe the addition of a table to sum up the different signs and symptoms with the different age groups would help. This section seems incomplete to me, where are all your references?

• Diagnosis needs some more detail and possibly an image (for completion)

• The ‘signs and symptoms’ in the Treatment section aren’t really consistent/parallel with the ‘signs and symptoms’ section itself. This could be improved by adding a similar table in the signs and section sub-heading outlining the same ‘signs and symptoms’ (just an idea)

• Glossary needs a lot more definitions.

--[[User:Z3289829|z3289829]] 02:43, 29 September 2011 (EST)

*Intro: Like the hand drawn figure but it’s not explained and most importantly, the Image is not referenced at all. Define methylation perhaps- it’s not a good idea to have introduction with a lot of terminology because you will lose your audience if they can’t understand the initial part f the page. The description of features is brief and good way to introduce the disease, it would help if you could use an image of an affected patient instead of the chromosome (which can be sued in the etiology section)/

*History: Love the colour but perhaps add a few more events, it looks very short. You can link your bolded words to a glossary.

*Epidemiology: The “screening” section doesn’t belong here. The section explained in dot points is not referenced at all. The image is great, but there is no references to the original image or any explanation of the image itself. Genetic counselling subheading also doesn’t belong in this section.

*Etiology: Clear and easy to follow but there are words that need defining in the glossary. The section would benefit if the image of the chromosome was moved here. Perhaps more explanation on the FMR gene. The first image could do with a bit more explanation. There are words in there eg: 5UTR that are not easy to understand.

*Development of disease: Good, the subheadings help and its well-formatted. Need a picture explaining the development.

*Signs and symptoms: The image is great, you can use this as your introduction to make it a bit more engaging. You should also make it bigger and explain the distinguishing features. The research is thorough!

*Diagnosis: Very short, needs more detail.

*Treatment: Love the colour, very detailed

*Glossary: Needs a lot more work! There are many words that you will need to define. For example “ allele, permutation, asymptomatic...” list goes on.

*Reference: What’s happening in references 3-8? That’s not proper referencing format. Number 41 reference – a link isn’t a reference.

*Overall: You keep referring to the disease as either fragile X syndrome or FXS. It’s best to stick to one or the other to avoid confusion. Need more interesting images. Some excellent research but it could do with a bit of work. Good job so far.

--[[User:Z3290270|z3290270]] 02:31, 29 September 2011 (EST)

'''Group 5'''

Introduction: Good pictures but they need to be bigger. Also, this section seems like a brief summary of the sections to come. I think it would be good if you included some more general background information on fragile x.

History: This section could be longer. The table would look good with some pictures in it.

Epidemiology: Great section and I like the diagram but some of the words in the diagram are hard to read.

Genetics: This section is reasonably well explained. The genetic terms need more explaining though.

Development: Good section but needs some pictures.

Signs and symptoms: Great section. Well written, flows well and easy to understand. Needs more pictures though.

Diagnosis: This section seems a bit short. Maybe you could explain how the diagnostic techniques work.

Treatment: The table seems too text heavy. Maybe add some pictures to break up the text.

Recent research: overall, good section. --[[User:Z3291324|z3291324]] 23:23, 28 September 2011 (EST)

Group 5

Hi, I can see some progress on this page which is good, content is interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: What is FMR1 gene? Need more information here, as in when was it first discovered, some stats
#* Epidemiology: I think screening information is extensive enough to be a section on its own
#* Etiology: no explanation of FMR1 gene so far, what is its normal function? Also, please refer to images used in this section
#* Development of the disease:nice succinct, easy to follow section. Perhaps add an image for one of the stages mentioned here?
#* Signs: REFERENCING!!! But, content is good and interesting
#* Diagnosis: An image here would be nice, and an explanation of how the technology is used to diagnose FXS
#* Treatment: Nice table with good information
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to balance out the text and image ratio, some good subheadings
#Content is correctly cited and referenced.
#* poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* I feel more research needs to be done here
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#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.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* Although the content is here, there is still a lot of work needed to make this page feel complete
* glossary is very lacking in terminology
* need more images
* further research would be nice to explain this disease in more detail

--[[User:Z3291643|z3291643]] 22:56, 28 September 2011 (EST)

'''Group 5:'''

•The introduction lacks referencing and is a little short, but good use of the images to gain the attention of the reader though as I was reading it I would have preferred for the images to both be on the right hand side.

•The student drawn image on the right is not explained very well and does not contain the correct copyright information.

•Is the diagnosis section finished? It seems a little short and lacking in detail, maybe add some more information to this section, perhaps also an image to help build up this heading and make it more balanced with the other sections.

•Glossary is incomplete and should be in alphabetical order

•References are repeated, but good work on the research

•Overall I liked the formatting of the page, it is easy to read visually appealing and a good use of images to balance out the text.

--[[User:Z3332183|z3332183]] 21:28, 28 September 2011 (EST)

'''Group 5'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there and well described.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Future research is well researched, but is there any other research possibilities that are on going to show breath of research? Glossary needs to be expanded - FXS as an acronym needs to be put there. Table in treatment has too much text. Put the text outside the table and use the table to summarise the content. The information in diagnosis is too brief and could go into a table. Consider expanding that section and provide more information on how and why the techniques diagnoses FXS.

'''*Content is correctly cited and referenced.'''
File:Fragile site appearance and distribution.jpg needs to be correctly referenced. Duplication of references need to be fixed. Emotional characteristics, Language and Speech, Physical phenotype and Physical phenotype section needs references.

'''*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.'''
no explanation given for File:Fragile x chromosome..jpg. more images would be good (Eg: in Fetal Development section maybe include an image of what a fetus looks like who has FXS?)

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Decent reference list and good in-text citation but is missing referencing in some areas.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Fetal development detailed.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has followed the guidelines but some changes would be good.

--z3329495 21:17, 28 September 2011 (EST)

'''GROUP 5: Fragile X Syndrome'''
*Info in the intro is ok but could be improved by maybe including more of an explanation of the CGG codon (some may not know what a codon is and what this implicates) and a small sentence on FMR1 gene
*The placement of the two images in the introduction is a bit weird, it disrupts the end of this paragraph. Consider just putting them on the same side or putting one of them in a different section
*I don't think the first sentence of the history section is history related, looks like it could be better placed in the intro
*Timeline is ok but could possibly be researched more to include more dates, but it's good that it goes up to 2010
*I don't know if Screening/Population testing goes under epidemiology, i think it's more part of management/diagnosis
*Etiology info appears clear and concise, maybe the image of the gene would be better placed in this section
*I find the section development of disease informative and summarised well. I like the way it's structured (subheadings are fitting), an image could improve this section
*Signs and symptoms looks like its been researched extensively, info is comprehensive and summarised well, a graph or another image could improve this section and balance out the text
*Physical phenotype has no referencing (where did this info come from?)
*Diagnosis is very underdeveloped, a lot more explanation is needed for these diagnostic techniques, images could also help improve this section
*Treatment is well researched, use of a table here is suitable, however maybe you could break up the writing by splitting up the Treatment Option and Description into two different sections of the table
*Recent Research is ok, a good intro paragraph may improve this section, maybe provide more recent developments

Overall:
*Glossary is incomplete and many words need explaining, consider linking the highlighted words to the glossary as an improvement, also it might be a good idea to include acronyms in the glossary as well
*legends of images could be expanded a little more
*Reference list needs some work, I don't think links to websites are the proper way to reference

--[[User:Z3331556|z3331556]] 21:15, 28 September 2011 (EST)

'''Peer Assessment Group 5-Fragile X Syndrome'''
*The introduction contains a little bit of heavy info in it. You might want to introduce the complex concepts e.g.methylation of the CGG triplet so the reader can ease into the page.
*The absence of references in the introduction makes it feel unreliable.
*The History seems to be succinct, good work.
*Nice diagram in 'Epidemiology', however it is missing a description and copyright information
*Avoid the italics as it makes the page look inconsistent as you dont have italics very often throughout
*'Development of Disease' is divided well into distinct sub headings, easy to follow
*'Signs and Symptoms' is heavy with too much information, can you summarize some of it to condense the whole section. Also maybe consider finding some images to give it a better balance.
*'Diagnosis' requires a little more explanation of what is involved in the different types of methods.
*The table in 'Treatment' needs division of the second column maybe into treatment option and a separate description just to make it look less heavy
*'Recent Research' is structured nicely, makes it a lot easier to read
*The definitions in 'Glossary' are inadequate
*Avoid italics in the glossary
*The reference list needs some major reformatting
--[[User:Z3308968|Tahmina Lata]] 19:43, 28 September 2011 (EST)

'''Group 5: Peer Assessment'''
* Your page looks a bid 80's with all the different pinks in your table. Not a bad thing, however may be just one colour per table would be enough
* The introduction is too brief and written a little careless and lacks referencing.
* The history table is good in the way that it's chronologic and easy to read but you could write a bid more about the relevance of these events.
* Your drawing needs some copyright information and if the writing would have more contrast it would come more into account.
* The aetiology section is informative overall but some long sentences could be separated and more explanatory. Put the pictures on the same side may be to give it a bid more shape.
* The development of the disease section and signs and symptoms section read well and there is good use of subheadings.
* Is there some current research you could talk about?
* Your glossary and your references clearly need some editing and fixing up
* Overall your page seems to be written a bid careless but there are bids of interesting information in there. --z3279511 17:10, 28 September 2011 (EST)

'''Peer Assessment #5'''
*Intro looks funny with a pic on each side of the text – reconsider this formatting. Maybe both on one side and one under the other?
*Intro 1st para is very detailed for an intro- perhaps explain it more, or in more general terms. The detail will come later
*The intro sentence in history would be better in the intro.
*You keep referring to the FMR1 gene, but I have no idea what this is or how it is relevant. Please explain it somewhere! Maybe have a short para just on it and explain about it.
*In signs and symptoms, are ‘emotional characteristics’ and ‘language and speech’ meant to be their own subheadings, or subheadings of ‘intellectual development’?
*Diagnosis section is not complete, needs a lot more info and explanation of the techniques, how they work, why they are used/relevant. – Modified PCR section is too wordy.
*Treatment table is good, can you stretch it so it takes up the whole box instead of being centered? Would look better
*Recent research – surely there is more you can discuss/other areas?
*I’m sure everyone else has mentioned it, but the glossary needs work. Really, just define lots of the ‘big’ words, as you can’t assume everyone knows what they all mean.
--[[User:Z3332824|z3332824]] 11:59, 28 September 2011 (EST)

''' Group 5 Peer Assessment'''
* First student figure has no explanation as to what it's all about, and is a pretty simple diagram. What does it contain? Where is your copyright information? The same can be said with the second student-drawn figure. Make sure this is fixed!
* The introduction section appears to be pretty short. Try to keep away from using the brackets and just enter your information in a continuous format.
* The headings and subheadings work quite well. However, the lack of images in the signs and symptoms section make this difficult to read; it seems like a large block of text without anything to assist in the breakup of the page (making it difficult to read and easy for us to lose attention).
* Subheadings are used quite well. The treatment section is well presented in table format, but once again, any images to help break things up?
* The recent and future research section doesn't seem to be completed. Is there anything that can be done for the future of the disease? Is it related to any other disease processes? The glossary also seems short and isn't in alphabetic order. Please add all the terms to the glossary to ensure that there is completeness of the project! There are many terms that are difficult to understand, so slot them in here.
* There just needs to be more work done overall to ensure that the project flows smoothly and all the smaller details are accounted for. At the moment there is still a large part of the project that feels quite sketchy and requires more work.
--[[User:Z3288827|Leonard Tiong]] 10:33, 28 September 2011 (EST)

Group 5: Fragile X
*Introduction: Maybe a bit too concise, some of the content that should be in the intro is missing. Maybe this should be redone with references! Also, it doesn’t draw the reader’s attention unfortunately.
*History: Simple table, but a small explanation regarding the significance of the discoveries would be very helpful.
*Epidemiology: Nice picture, had to tilt my head a little. The “Screening/Population testing” seems like a whole new section itself. Might have to look into that?
*Etiology: This section was very well managed.
*Development: I like the subheadings, maybe an image to help add some visuals, but not required.
*Signs and Symptoms: This again, was well done, though detailed, the mass text was slightly disorientating, another image perhaps?
*Diagnosis: Looks incomplete, more info required, probably another sub-heading would do.
*Treatment: Best section in this webpage. Detailed and neatly laid out.
*Glossary: Some explanations and a few more words added here would do the trick!
*Overall: The basic fundamentals are there, some more info here, and a few tweaks there is all that is needed! Keep it up.
--[[User:Z3332327|Lisa Xiao]] 01:25, 28 September 2011 (EST)

'''Group 5'''

*Introduction should be explained a little better and also referenced
*Hand drawn image needs the correct referencing/copyright info
*Good use of subheadings in epidemiology
*Etiology is a little hard to follow
*Development of disease needs an image to break up the text
*Signs and symptoms is very text heavy- try to change it up a bit i.e. use of dot points
*Good use of table in treatment
*Glossary needs to be extended
*Overall, this has potential to be a good project with a few adjustments

'''Group 5'''

*Introduction: too much detail, give an overview. Only one of the images would be enough.

*History: well done

*Epidemiology: screening / population testing should be a separate section, very good image

*Etiology: well done,

*Development and Symptoms: both sections are clear and easy to follow, good use of subheadings

*Diagnosis: seems incomplete

*Treatment: very detailed

*Research: I would add some other examples. If you want to outline only autism, maybe change the heading.

*Glossary: there is a lot missing

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 21:31, 27 September 2011 (EST)

'''Group Peer assessment'''
*Introduction images placement may work better on one side or below the information though current placement is confusing affecting text as well.
*History requires more elaboration as well at least indication of the founder in the introduction of the history even an image of the founder would benefit this section, although the timeline is nicely done.
*Development and disease would be better as a sub heading under eitology as development of the disease links with the causation of the disease.
*Glossary needs work done as most terms are genetic related and those without a genetic background will find difficulty understanding the web page.
*Referencing only needs to adjust the links, links need to be sited properly manually.
z3332250 23:50, 26 September 2011 (EST)

Group 5 Peer Review

*Introduction does not entice the reader to read the rest of the page. Maybe less scientific language in the introduction?
*Table under history is well presented and visually appealing
*“Postnatally” and “postpubescent” need to have “development” added to the subheadings
*Well referenced
*The consistent colour scheme throughout is a nice touch
*Another image under signs and symptoms would make this section look more balanced
*Diagnosis seems brief-add information or perhaps merge with another subheading
*Glossary needs to be expanded
*Logical, clear and organised structure
*Overall, a good page. The bulk of it is there. If each section just changed some minor things, this page would improve greatly.
--[[User:Z3308965|Fleur McGregor]] 19:38, 26 September 2011 (EST)

'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it could be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

--Z3389806 07:34, 26 September 2011 (EST)

'''Group 5 Critique'''

#• Introduction should not contain clinical manifestations. It should introduce the topic as a whole. This section needs to be re-written
#• The history section is ok. The timeline could be explained a little better to give a clearer view of what the history of the disease is to the reader
#• Epidemiology should not contain the advantages and disadvantages of population testing. This should be another section in itself
#• Aetiology was fine
#• Development of the disease was ok
#• Signs and Symptoms was good
#• Diagnosis needs to be more detailed than what it is
#• Treatment and recent research is impressive
#• Glossary needs more terms added to it. It is too short, however that will be fixed when you add more explanations to the other sections and define the terms here.

--[[User:Z3289991|Robert Klein]] 18:57, 24 September 2011 (EST)

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

* I liked your page as it had a simple and easy-to-follow lay out
* Some of the images could have been made larger on your actual page just so that it adds dynamics to your page
* I was left wanting to know more about the diagnosis, this section was quite brief
* I personally found your treatment table hard to read because there was so much information. Personally I believe that maybe dot-point form could have been used to get your main points across.
* Perhaps expand upon your glossary as there were some words that weren’t in there that maybe should have been.
--[[User:Z3332629|z3332629]] 15:25, 22 September 2011 (EST)

'''Group 5 Assessment'''
*The Fragile X Chromosme. Jpg needs both an explanation and referencing.
*There is no referencing in the Introduction section. Where did you get this information from?
*History- Good idea to setup using a chart to organize the data. First time I’ve seen that.
*Fragile X Inheritance jpg looks great!!! Way to incorporate the data into a figure. However, it does still need citing.
*Not all the information in the Screening/Test Population is cited. Where is this information referenced from?
*The Development of Disease portion could use a figure or two to make it more appeasing to look at.
*Some of the information under Signs and Symptoms is also not cited. Where was this information drawn from?
*Good chart under the treatment section. However, maybe try a bullet list on the right hand column to help set the ideas apart from each other?
*The glossary link seems a little short… Are you sure there aren’t any more words which would be helpful to define for the audience?
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
*Overall, good work! Just work on the referencing and some of the visual aspects.
--[[User:Z3391078|Z3391078]] 15:09, 27 September 2011 (EST)

Group 5
* Straight into it hey- a little bit more of an “introduction” might help sorry. The first line kind of scared me. Yes it is relevant information but I think you need to almost ‘warm the reader up’ if you know what I mean. When reading anything I don’t think jumping straight into the nuts and bolts of how it works benefits anyone. I think you should start with what it is and why it is important that the reader learns about your topic
* The history section is brief and I don’t actually understand the relevance of the discoveries. While putting the information in a table shows that you know how to format it to look pretty, it is not the most effective way of showing
* Your hand drawn images still need to be referenced and copyright put on them
* Reading through I am overwhelmed by the content. This may be due to a lack of proper introduction or early explanation. I feel like the information isn’t as accessible as it could be
* Development of the disease would work well in a table I think
* Maybe put the clinical manifestations into dot points? I just feel like everything is a bulk of text and it would be better if you broke it up a little
* An image in diagnosis would help
* Treatment works well in a table
* Glossary could be extended
* You are on the right tract it is just a very heavy project. The content is all there but I found it really hard to get through.

'''Group 5'''
* Great structure with headings and subheadings, very easy to follow and read.
* Nice succinct intro. good over view of the disease. - Maybe you could dot point phenotypic abnormalities
* Some areas a little text heavy, additional pictures would fix this problem. for example some more pictures in signs and symptoms.
* Good simple history, well researched. easy to follow.
* Maybe Screening/Population testing could be its own heading.
* Great section on development of disease! I like the format very interesting relevant information! well done!
* Treatment section well put together but a little text heavy- try condensing info or bullet points.
* Make sure all the pictures are referenced properly.
* Nice to see your references grouped.
* NIce student drawn picture.
* Make sure all your acronyms/ scientific lingo is in the glossary.
* I liked that you has a continuous colour scheme for your tables. It makes your page look very neat.
* The bottom of the page is a little text heavy.

*'''Introduction''': Concise and to the point.
*'''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.
*'''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.
*'''Screening/Population testing''': Looks fine.
*'''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.
*'''Development''': Well explained, good use of subheadings.
*'''Signs and Symptoms''': Also well explained, good use of subheadings.
*'''Diagnosis''': Too short. What about non-genetic diagnosis?
*'''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?
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?
*'''Glossary''': Too short, more terms need to be explained.
*'''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.
*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?

'''Group Project 5'''

*The introduction was too in detail and did not seem like an introduction. Also there are no references ?
*the history is easy to read
*Etiology - very nice section of information
*Development of the Disease - was a good idea to put this in and the information is easy to read, maybe include some hyperlinks to the glossary?
*The treatment table is quite informative and easy to read due to its structure and quite appealing to the eyes
*More should be added to the glossary

--[[User:Z3330313|z3330313]] 20:02, 28 September 2011 (EST)

'''Peer Assessment: Group Project 5'''
*The introduction has no references.
*More pictures in the sections on development, signs and symptoms and diagnosis would help to make the written work easier to follow. Examples of pictures that could be added are images of neural crest development put in the development section or images of diagnostic techniques in the section on diagnosis.
*The section on treatment is clear and informative.
*The different diagnostic procedures could be explained more, such as how they are each conducted.
*Instead of having the uncommon words highlighted in bold, maybe you could link the words to their definition down in the glossary section.
*Some of the references are duplicated. They can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
*In conclusion, this project is both accessible to people who have no great scientific knowledge, but also delves into quite specific knowledge. A good balance.
--[[User:Z3217345|z3217345]] 21:59, 27 September 2011 (EST)

'''Peer Review'''

* the layout was not well structured
* was able to understand the disorder

--[[User:Z3060621|z3060621]] 21:31, 28 September 2011 (EST)

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{{2011GroupDiscussionMH}}

=='''Discussion'''==

Hey,
I'm under the impression that he is closing it tomorrow at 5pm.
Also, make sure you aren't editing stuff out. (Tara, im looking at you :P you edited out some of my stuff, but it's all good).
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

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'''BORIS!'''
This is what you missed in todays lab: you need to read through the peer review comments and work on the comments that are applicable to your section (although you don't have to agree with all the comments), it is also now time to work on all the sections together and we still need more pictures (make sure they are referenced properly and include the student template - if we have any material not cited properly, Mark is going to delete it), we also need to look into maybe adding videos to our page and Sandra would like us all to contribute to the recent research section. We have 2 weeks to finalise our wiki and our page will be closed at 11am two Thursdays from now. Thanks!

--[[User:Z3290815|Tara Lofthouse]] 19:13, 29 September 2011 (EST)

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Collins SC, Coffee B, Benke PJ, Berry-Kravis E, Gilbert F, et al. (2010) Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype. PLoS ONE 5(3): e9476. doi:10.1371/journal.pone.0009476

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Nice work Sandra! I will keep looking and i see you changed your table to pink too haha --[[User:Z3290815|Tara Lofthouse]] 20:54, 18 September 2011 (EST)

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Hey guys, i have just edited our group page and put up 3 pictures! Please try to find more before Monday (especially under development of the disease and signs and symptoms as these parts are so dense with writing and thus need pictures to break it up a little bit)! Cheers, --[[User:Z3290808|Sandra Issa]] 00:24, 18 September 2011 (EST)

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Here:

http://3.bp.blogspot.com/-88xXtruHpyo/TlaALBe6CaI/AAAAAAAABx8/ZMdZULFKEns/s1600/happy%2Bcamper.jpg

{|
|-
| Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)
| 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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.
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.
Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients). Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.”
|-
| Treatment of Mood Instability and Aggression
| 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.
Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”
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.”

|}

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Hey guys, yep i will be there at 10 count me in! --[[User:Z3290808|z3290808]] 09:42, 15 September 2011 (EST)

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It looks like it is going to be late nights all round. We should try and pump out an intro in that time tomorrow as well as at least one image? --[[User:Z3290815|Tara Lofthouse]] 18:52, 14 September 2011 (EST)

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Okay, Tomorrow at 10am it is. I'll finish my stuff off tonight (it looks like being a late night :P).
I'm assuming that it doesn't have to be perfect by tomorrow. It just needs to look alright, so that people can give us feedback before we finish it, yeah?
Also, Boris, Interview is on the 27th. I was just visiting a friend. I'll tell you how it goes though, when it does happen. --[[User:Z3290618|Ziggy Harrison-Tikisci]] 17:43, 14 September 2011 (EST)
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I can make it at 10am on Thursday as well --[[User:Z3290815|Tara Lofthouse]] 12:08, 14 September 2011 (EST)

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Ooo, interview? How'd it go?
I don't have time to meet up today (Wednesday), but I can see you guys in the lab at 10 tomorrow, before the class.
--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)

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Hey Guys, Sorry I've been in Melbourne for the week, so haven't done any work. Getting on it now. Going to do all my referencing, editing etc.
Wanted to ask if there is a time when we can get together, go through it all and make it pretty. Did we just want to do this before our lab on thursday, or if you guys have some time on wednesday afternoon?
Furthermore, how harsh is the criticism/feedback? Doesn't mince his words, does he? --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:51, 12 September 2011 (EST)

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Hey Boris yes i am experiencing the same problem. I cannot see the references and the reference list looks like a bunch of arrows facing superiorly. I got a bit worried but then checked the other groups and they had the same issue. I'm not sure what we can do? Let me know. ---[[User:Z3290808|Sandra Issa]] 09:49, 9 September 2011 (EST)

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WHAT HAPPENED TO OUR REFERENCES. Can you guys do me a favour and tell me if you can see them? I was trying to put in an image just then and when I did the save it came up with references wiped. I tried undoing my last edit to no avail. There are still 30 something references, there's just nothing IN them. When I finished my word edit earlier today I actually saved the ENTIRE script as a word document; when I tried to rewrite EVERYTHING with that same (working) script it still came up with stuffed up references.

Let me know if you guys see the same problem. If you do, I'll have to get in contact with Mark Hill to fix the script.
--[[User:Z3290689|Boris Zolotarev]] 23:31, 8 September 2011 (EST)

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I hate how the times shown on the editing thing are totally out of whack....can I post anything up at the moment? ><
--[[User:Z3290689|Boris Zolotarev]] 23:27, 7 September 2011 (EST)

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Hey guys, i have just added the diagnosis part of our page and have also finished the treatment. Let me know if you think the treatment is too long? Or if you want to make any changes to the "Recent Research" part of our page.

Also, i will add in more references for this part very soon. I have put in a general reference (review article) but will make sure i include all references used very soon.

Have a good night, --[[User:Z3290808|Sandra Issa]] 21:16, 7 September 2011 (EST)

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Suggestion: rename '''Development of disease''' to '''Progression of disease'''. Also, I should have a heap up later tonight, I'm compiling it all in a separate document at the moment.

--[[User:Z3290689|Boris Zolotarev]] 15:39, 7 September 2011 (EST)

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Hey guys, just letting you know that i have found a great article which addresses many current 'treatments' for FXS. Also, i have found another article which summarises the current methods of diagnosing FXS. I will add this information (what i think is most relevant from the articles) onto our group page under the headings "treatment" and "diagnosis" '''very soon'''. Please feel free to add in anything that you believe i have not addressed under these headings. Also, i will try to edit our page as a whole soon so that it looks more uniform in appearance. Over the next couple of days we should all read each of the sections and try to add in additional information that someone else may have missed. Also, a reminder to keep an eye out for relevant pictures that have unrestricted access to add onto our page!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:32, 5 September 2011 (EST)

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Hey, I'm doing a whole bunch now. I'll properly reference it all later, but I'm getting a lot of it off the american National Institute of Health. They've got references for all of it. So when I have more time, I'll go through those references, add them, and edit the information. So, what I put on the group page will just be an overview. Also, you people should go to bed earlier :)
http://www.nichd.nih.gov/publications/pubs/fragileX/sub6.cfm
--[[User:Z3290618|z3290618]] 09:49, 1 September 2011 (EST)

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z3290808: I don't know why it wouldn't let you save, i wasn't editing at that time. Try again and if it doesn't work maybe paste your work here with your references and one of us can put it onto the project page for you?

Boris: At least something is up :) My section needs a lot more editing and a lot more cross checking with other references as well.. Any progress is good progress at the moment
--[[User:Z3290815|Tara Lofthouse]] 03:35, 1 September 2011 (EST)

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Heya, I took a stab at my section but I'm a bit dead at the moment '''(points to timestamp)'''. I'll try get some more done tomorrow between the lecture and lab.

On the plus side, I added another 6 or 7 references to our thingy ^^

--[[User:Z3290689|Boris Zolotarev]] 01:28, 1 September 2011 (EST)

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Guys it's not letting me save what i have written onto the group page! Is anyone currently on and trying to edit at this same time?
--[[User:Z3290808|z3290808]] 22:41, 31 August 2011 (EST)

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Yo Boris, You do Etiology, I'll do signs and symptoms. We can work towards the middle.
That leaves history and epidemiology to Tara and Recent research to Sandra. And then we can all refine it/make an intro.
We can at least do that to start with.
Also: can everyone contribute to the glossary. If you find any terms that people (eg. me) wont understand, please keep them.--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:10, 25 August 2011 (EST)

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The only reason why we need to put our names down now is to satisfy the weekly individual assessment but of course we can change things. Just put your name down for epidemiology or whatever was left over and we'll discuss it tomorrow. Maybe if we could get to the lab 10-15min earlier because we never get enough time at the end of the lab?

--[[User:Z3290815|Tara Lofthouse]] 19:50, 24 August 2011 (EST)

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Just skimmed through this (damn I left it late >< ), should I nominate something now or should we discuss it tomorrow?
Also, what do you guys think of having some sort of realtime chat method? Facebook or something of the sort...
--[[User:Z3290689|Boris Zolotarev]] 19:17, 24 August 2011 (EST)

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Yeah i know but the ones i put my name down for are really not that lengthy. We definitely need to have a chat tomorrow.
--[[User:Z3290815|Tara Lofthouse]] 17:45, 24 August 2011 (EST)

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Hey guys, you haven't left much for Boris and i to do lol .. I don't mind doing the recent research part - focussing on autism and fragile x.. but then i don't know what Boris would do? I will sign my name for now but i think we will have to change it around a little to better make the work load equally spread.

Cheers, --[[User:Z3290808|Sandra Issa]] 16:17, 24 August 2011 (EST)

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I've taken it all on board and changed it. I'm fine for you to do whatever you want but doing both the genetic component and the signs and symptoms might be a lot of work. As long as everything is spread evenly i don't mind :)

--[[User:Z3290815|Tara Lofthouse]] 16:35, 23 August 2011 (EST)

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Hey, I was wondering if anyone minds if I do 'Genetic contribution'. Also, is it okay if I follow the timeline of the disease? I will start with the chromosome, saying what the defect causes at a molecular level, and then when it first presents, and how it affects the development etc up until how it presents in the adult. Which means I'd probably do "Signs and symptoms (clinical Presentation)" as well.
ALSO, we need to do a brief history of the disorder. So, below I've just tweaked the layout Tara and Sandra put up: let me know what you think

* Introduction
* History of Disease
* Epidemiology
* Etiology
** Genetic contribution
* Development of Disease
** Fetal Development
** At birth
** In Adult
*** Signs and symptoms
* Recent research
** Fragile X and Autism
** Diagnosis
** Treatment
--[[User:Z3290618|z3290618]] 15:18, 23 August 2011 (EST)

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Yeah, i think it makes sense how you've got it Sandra. However like Boris said maybe instead of having the heading "Autism and Fragile X Syndrome" maybe we could have recent research/current studies or something along those lines and include it there along with diagnosis and treatment? Do you think that etiology is too similar to genetic contribution?

ALSO!!!
What headings would you like to research? I set up a "Who's doing what?" heading on this page to sign your name next to.

--[[User:Z3290815|Tara Lofthouse]] 12:39, 23 August 2011 (EST)

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Hey guys, i have come up with a couple of headings that we can use:

* Introduction (short summary)
* Epidemiology
* Signs and Symptoms (Clinical Presentation)
* Etiology
* Genetic Contribution
* Autism and Fragile X syndrome
* Diagnosis?
* Treatment?
* References

Tara i also like the format that you have included below.. i basically have made something similar but in different order based on what i think should come first perhaps? The ones with a question mark beside them are ones that i am unsure if we should include or not. Let me know what you think!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:03, 23 August 2011 (EST)

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Hahaha of course it's your place to say so.. good suggestion, i'll fix it up now and if we want to change it again than that's no problem. I just thought i'd put something up to get started and we can go from there. What i've done is no where near completed.
--[[User:Z3290815|Tara Lofthouse]] 18:52, 22 August 2011 (EST)

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(I know it's not my place to say so before I've submitted my own suggestion but) I think I'd put "Autism and Fragile X Syndrome" within the "recent research" subtopic. I'll put up a suggestion by tomorrow evening, if not earlier.
--[[User:Z3290689|Boris Zolotarev]] 09:27, 22 August 2011 (EST)

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'''Hello everyone,''' what do you think about using the following headings for our project? Are there ones that you think we could omit or ones that you would like to add? We also need to decide on who is doing what.
* Signs and symptoms
* Diagnosis
* Genetics
* Etiology
* Epidemiology
* Treatment
* Recent research
** Autism and Fragile X Syndrome
* References

--[[User:Z3290815|Tara Lofthouse]] 16:26, 21 August 2011 (EST)

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[http://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Lab_2_-_Group_Project Group project] --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:58, 4 August 2011 (EST)

[http://www.ncbi.nlm.nih.gov/omim OMIM]--[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:59, 4 August 2011 (EST)

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Here's another interesting topic.

[http://en.wikipedia.org/wiki/Apert_syndrome Apert Syndrome aka acrocephalosyndactyly] --[[User:Z3290689|z3290689]] 11:38, 11 August 2011 (EST)

=='''Congenital Hypomyelinating Neuropathy'''==

What do you guys think you of this topic [http://omim.org/entry/605253 Congenital Hypomyelinating Neuropathy]?

There are quite a few articles on it:

Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination.

Analysis of congenital hypomyelinating Egr2 Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination.

P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves.

Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg–Hirschsprung disease: Phenotypes linked by SOX10 mutation.

A lot of them overlap with their findings and the focus of their studies, so it seems to be a pretty thorough topic.

--[[User:Z3290689|Boris Zolotarev]] 21:03, 7 August 2011 (EST)

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I’m all for doing '''Congenital Hypomyelinating Neuropathy''' as our topic.

Here are some articles I have found:

'''Research Articles:'''

[http://neuro.cjb.net/content/29/8/2312.full.pdf+html Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure in Mice Carrying the Egr2 I268N Mutation]

* 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

[http://jnnp.bmj.com/content/48/12/1269.full.pdf Congenital hypomyelinating neuropathy]

* 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:'''

[http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TBD-3W37BMX-C-1&_cdi=5140&_user=1975841&_pii=S0887899498001386&_origin=&_coverDate=03%2F31%2F1999&_sk=999799996&view=c&wchp=dGLzVzb-zSkWA&md5=d2e9e64dfc821d71ec81675f01932b8a&ie=/sdarticle.pdf Congenital hypomyelinating neuropathy: two patients with long-term follow-up]

* 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

--[[User:Z3290815|Tara Lofthouse]] 12:22, 9 August 2011 (EST)

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=='''Fragile X Syndrome'''==

==='''Articles'''===

Hey guys,
I had a look at Congenital Hypomyelinating Neuropathy and to be honest i did not find it very appealing. I found the disorder "Fragile X Syndrome" to be very interesting! Can you guys please check out the following link on [http://www.fragilex.org/html/cause.htm/ Fragile X Syndrome] and let me know if the disease also interests you!? I found the information on it is quite extensive and the disease is well known. If you do not want to base our project on this syndrome, i am sure we can decide on one we can all enjoy studying! :)

Here are some interesting articles that i have found on '''Fragile X Syndrome''':

* '''Review Article''': Fragile X syndrome: from gene discovery to therapy <ref><pubmed>21196228</pubmed></ref>

- This review focuses on the molecular and biochemical pathways shown to be relevant in the Fragile X Syndrome. It describes that a mutation in the FMR-1 gene was found to lead to Fragile X Syndrome due to excessive repeats of the trinucleotide sequence CGG which is known to inactivate the FMR-1 gene, making the X chromosome fragile and prone to breakage. This review article also demonstrates the many vital functions of the FMR-1 gene such as its role in RNA transport and stability, thus absence of the protein transcribed and translated from this gene is thought to affect brain development and thus leads to signs of mental retardation.

* '''Research Article:''' DNA methylation represses FMR-1 transcription in fragile X syndrome <ref><pubmed>1301913</pubmed></ref>

- This research article explores the two molecular differences of the FMR-1 gene in normal individuals vs. those with Fragile X Syndrome. These differences are an increase in size of an FMR-1 exon containing a CGG repeat and abnormal methylation of a CpG island 250 bp proximal to this repeat. This research article also shows how these two abnormalities repress transcription of the FMR-1 gene, leading to the absence of the FMR-1 protein which is thought to be the contributing factor to the Fragile X phenotype.

--[[User:Z3290808|Sandra Issa]] 19:53, 9 August 2011 (EST)

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Here are some articles I have found for '''Fragile X syndrome''':

'''Research Article:''' The state of synapses in Fragile X Syndrome <ref><pubmed>19325170</pubmed></ref>

* Fragile X Syndrome is the most common inherited form of mental retardation and a leading genetic cause of autism.

* Evidence that suggests alterations in synapse number, structure and function are associated and contribute to both Fragile X Sydrome and autism.

* Fraile X Syndrome is caused by loss of function of the Fmr1 gene which encodes the RNA binding protein, FMRP (FMRP is present at synapses where it associates with mRNA and polyribosomes).

* FMRP is also has a role in synapse development, elimination and plasticity.

* An understanding of the molecular and synaptic function of FMRP, as well as the consequences of its loss, has led to the early developments of therapeutic strategies for Fragile X Syndrome.

'''Research Article:''' Fragile x syndrome: history, diagnosis, and treatment. <ref><pubmed>6348096</pubmed></ref>

'''Review Article:''' Systematic review of pharmacological treatments in fragile X syndrome <ref><pubmed>19822023</pubmed></ref>

'''Review Article:''' FMR1 and the fragile X syndrome: human genome epidemiology review <ref><pubmed>11545690</pubmed></ref>

--[[User:Z3290815|Tara Lofthouse]] 14:37, 16 August 2011 (EST)

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==='''Images'''===

[[File:FMR4 is silenced in fragile X syndrome.jpg|thumb|FMR4 is silenced in fragile X syndrome]]

[[File:FMR4 is silenced in fragile X syndrome.jpg|350px]]

File:FMR4 is silenced in fragile X syndrome

--[[User:Z3290808|Sandra Issa]] 10:20, 14 August 2011 (EST)

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[[File:Hippocampal_Formation.jpg‎|thumb|Hippocampal_Formation]]

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

File: Hippocampal_Formation

--[[User:Z3290815|Tara Lofthouse]] 13:49, 17 August 2011 (EST)

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Like?
[[File:Fragile site appearance and distribution.png|300px]]
File: Fragile site appearance and distribution
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 08:55, 18 August 2011 (EST)

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[[File:Journal.pone.0013559.g001.png‎|thumb|FXR1 (A) and FXR2 (B) crystal structures]]

[[File:Journal.pone.0013559.g001.png‎|300px]]

File: FXR1 and FXR2 crystal structures

--[[User:Z3290689|Boris Zolotarev]] 11:00, 18 August 2011 (EST)

== '''Who's doing what?''' ==

* Introduction = DO AT THE END!!!!
* History of Disease = Tara
* Epidemiology = Tara
* Etiology = Boris
** Genetic contribution<ref>http://www.fragilex.org/html/premutation.htm</ref><ref><pubmed>10208170</pubmed></ref><ref><pubmed>11445641</pubmed></ref><ref><pubmed>12638084</pubmed></ref><ref>http://ghr.nlm.nih.gov/condition/fragile-x-syndrome</ref><ref><pubmed>8348153</pubmed></ref>
** Development of Disease
*** Fetal Development
*** At birth
*** In Adult
* Signs and symptoms = Ziggy
** Physical phenotype
** Social interaction
**Intellectual development
* Recent research = Sandra
** Fragile X and Autism
** Diagnosis
** Treatment
* References

==ZIGGY'S STUFF==
Just leaving this here for the next hour, so that I don't have to retype it all (can't get wifi in the embryo lab).

The hallmark of the fragile X syndrome is mental retardation, which was noted as early as 1943 in a report of a large family with 11 mentally retarded males and two mildly retarded females. 64 The clinical phenotype associated with the syndrome has since been widened to include a variety of cognitive, physical, and behavioral characteristics (reviewed in Mazzocco). 65 Almost all males with the full mutation exhibit some clinical features of the fragile X syndrome. Also, most affected males do not reproduce, presumably due to the severity of mental retardation. With regard to cognitive function, affected males often exhibit developmental delay very early in childhood. By the age of 3 years, most males will test in the mentally retarded range. 66 Ultimately, almost all males with the fragile X syndrome are mentally retarded, with severity ranging from profound (IQ <20) to mild mental retardation (IQ 50–70), with most being moderately retarded (IQ 40–54) (reviewed in Hagerman). 67 Physically, adult males often have a long narrow face, prominent ears, a prominent jaw, and macroorchidism (reviewed in Hagerman). 67 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, and mitral valve prolapse (reviewed in Warren and Sherman). 8 Males with the fragile X syndrome also tend to exhibit behavioral features such as hyperactivity, social anxiety, perseverative speech and language, tactile defensiveness, stereotypies (e.g., hand-flapping), and hand biting (reviewed in Hagerman). 67 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. 68 The association of fragile X with autism, however, is not clear because the proportion of males with the fragile X syndrome meeting the diagnostic criteria for autism seems to diminish with age. 68

Physical phenotype
Before puberty, children with Fragile-X tend to have no discernable 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. 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 macro-orchidism: enlargement of the testicles. Fragile-X patients may also have loose connective-tissues, allowing their joints to be more flexible that normal. This may cause complications arising from increased risk of 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.

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. Their anxiety often manifests itself as discontinuous speech and a lack of eye contact.

Results indicate that compared to the control group, individuals with FXS exhibited decreased activation of prefrontal regions associated with complex social cognition, including the medial and superior frontal cortex, during successful face encoding. Further, the FXS and control groups showed significantly different relationships between measures of social anxiety (including gaze-fixation) and brain activity during face encoding. These data indicate that social anxiety in FXS may be related to the inability to successfully recruit higher level social cognition regions during the initial phases of memory formation.
Reference: Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome.

Intellectual development
As a generalisation, the majority of Fragile-X patients have an IQ between 1 and 2 standard deviations below the population mean. This equates to around 40-85. Few Patients lie out-side this range, with approximately 20% within the ‘normal’ range (85-115) and less below 40. Females however, show lower impairment, with only one-third having IQs within the ‘mental retardation’ range.
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.
Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points.

Studies of intellectual function in FXS often demonstrate a mean IQ decline of 4 to 9 standardized points over intervals ranging from several months to 13 years.
Reference: Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Working Memory
First, when individuals affected by the premutation are examined as a group, they exhibit a weakness only for tasks that reflect functioning of the central executive subcomponent of working memory.

Second, when both permutation sub-groups are examined together, the extent of the central executive deficit is significantly correlated with larger CGG repeat expansions.

For permutation males who are asymptomatic, mild executive dysregulation, inhibitory deficits that worsen with age, and declarative verbal learning and memory are notable.

The detection of a deficit in the central executive component of working memory in the fourth decade of life that progressively deteriorates with age suggests a cumulative process that may be a cognitive correlate to the underlying degenerative process identified in premutation males.

The significant correlation between CGG repeat length and central executive working memory in asymptomatic carrier males suggests greater neuropathology in carrier males with larger expansions in FMR1 mRNA transcripts.
Reference: Lifespan changes in working memory in fragile X premutation males

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.

== '''References''' ==
<references/>

2011 Group Project 5

2011-10-12T07:59:04Z

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{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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 premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Related Links ==

* http://embryology.med.unsw.edu.au/Defect/fragilex.htm

* http://embryology.med.unsw.edu.au/Notes/neuron2.htm

* [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development]

* [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation]

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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/>

----

{{2011Projects}}

2011 Group Project 5

2011-10-12T07:17:08Z

Z3290618: /* Signs and Symptoms */

{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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 post-natally; elongation of the face becomes more noticeable. Additionally, reports of mitral valve prolapse, reduced joint stability, flat feet, arched high palate and [[#Glossary | ''' Postural hypotension ''']] have been noted<ref><pubmed>6348096</pubmed></ref><ref name="PMID3953647"><pubmed>3953647</pubmed></ref>. Joint hyper flexibility, protruding ears and the [[#Glossary | ''' 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><pubmed>9421410</pubmed></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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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 premutation carriers present with a neurodegenerative disorder known as Fragile X–associated tremor/[[#Glossary | '''ataxia''']] syndrome (FXTAS). Past studies identified that rCGG repeats in Fragile X are enough to cause [[#Glossary | '''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 [[#Glossary | '''neurodegeneration''']] by identifying over 100 proteins that interact with Pur α, focusing on Rm62 which could modulate [[#Glossary | '''neurodegeneration''']] mediated by rCGG. This study shows that “rCGG repeats decreased the expression of Rm62 post-transcriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional [[#Glossary | '''mRNA's''']] 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 [[#Glossary | '''mRNA's''']] in the nucleus (most likely due to impaired nuclear export) could be a contributing factor to the pathogenesis of FXTAS.

== Internal Links ==

== 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.

'''Asymptomatic:''' if a patient is a carrier for a disease or infection but experiences no symptoms.

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

'''Atrophy:''' the partial or complete wasting away of a part of the body.

'''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/>

----

{{2011Projects}}

Talk:2011 Group Project 5

2011-10-12T07:05:22Z

Z3290618: /* Discussion */

{{2011GroupDiscussionMH}}
Just in case you guys couldn't find it!
--[[User:Z3290815|Tara Lofthouse]] 14:31, 11 October 2011 (EST)

===The final stretch!===

* The group projects will be locked after next weeks practical ('''5:00 pm''') for no further changes.
* You are free to make any changes you wish to the existing project page (additions, deletions, formatting etc).
* You should also go through all displayed uploaded files and make sure they conform to the information requirements I specified in today's practical (without the numbering):
# Correct image file name (describes what the image shows, keep it brief and to the point).
# Original legend information and any clarifying description that shows how it relates to your group topic.
# Correct citation format in its own "Reference" sub-sub-heading (if pubmed extension does not format correctly paste the entire text in and add a PMID number link at the end) You can also link to any other location of this citation, but this is not a requirement.
# The copyright information (Don't just paste, make sure it says that you can use then image).
# Finally include the student image template (copy the following in read mode, and paste in your image information in edit mode) <nowiki>{{Template:2011 Student Image}}</nowiki>

* You should complete all your updates ASAP and not leave everything to the last practical class where you will have limited time.
* We have a guest presenter for next week practical and '''I do not want any Group work during her part of the practical'''.
** Remember all edits are logged and time-stamped, I can see who has been editing when they should doing the practical.

===Last Addition to your Project Page===

* Is a new sub-heading entitled "Related Links".
* This sub-section should link to other pages on the embryology website that relate to your topic.
* Format as a bullet list, link first and a brief description (one line) of how it relates to the topic.
* An example is shown below.

==Related Links==

* [[Placodes]] - this page relates to today's practical as the earliest sensory specialisation visible on the embryo surface during week 4.

----

Hey guys, i have added some more recent/ future research into the corresponding heading! I have also added another picture under this heading. The research is very current (2011) which is good. Hope you guys like it :) --[[User:Z3290808|z3290808]] 13:37, 8 October 2011 (EST)

=== Sandra ===

SAAAAAAAAANDRA:

This is what it will look like: [[Week 2|this is how you make a link to a page on this website thingy bla]]

This is what you type in: <nowiki>[[Week 2|this is how you make a link to a page on this website thingy bla]]</nowiki>
* Where you're linking it from "Week 2"
* Description "this is how you...."

--[[User:Z3290689|z3290689]] 12:45, 6 October 2011 (EST)
----

==='''Discussion 2'''===

Hey, I'll be doing quite a few edits today/tonight. I'm putting up all of my references now.
Also, I'm going to be making sure all of our referencing is in the same format. I noticed there are a few that link the website for an article. I'll try to fix them up.
I want to just check with you guys if the following is okay:
I need to put on my student page what my contribution to the group project is. I'm going to put up "signs and symptoms" without the two pictures. The picture I put in the discussion in the first weeks (though someone else put it in the actual page) and finally the formatting for the tables (but in grey-scale as it was originally). Are there any objections for to that?
Let me know if there is anything else, and make sure you aren't accidentally editing out my edits if we're doing work :D
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

Hey guys, i have edited my diagnosis section - i have put it in a table and have found some relevant videos. Also, i will try to find some more recent research. It would be great if everyone can also pitch in to this section anytime you find some recent research that is relevant to our topic but not addressed in one of the subheadings.
To Ziggy - could you please finish off the referencing for your section Signs and Symptoms. Also if possibly, could you please add a photo to the group page. That would be much appreciated.
Cheers, --[[User:Z3290808|z3290808]] 11:59, 6 October 2011 (EST)

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_5_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_5_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

[[2011_Group_Project_5|'''Group 5''']]: [[User:z3290618]] | [[User:z3290689]] | [[User:z3290808]] | [[User:z3290815]]

----

=='''PEER REVIEW COMMENTS'''==

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
--[[User:Z3284061|z3284061]] 11:54, 29 September 2011 (EST)

'''Group 5'''

* The images might be better all on the same side
* An image is needed in Development
* "Signs and Symptoms" is a little text heavy and needs more references
* Diagnosis appears to be incomplete
* Glossary needs to be expanded
* Links to the glossary might be helpful
* Double referencing needs to be fixed
--[[User:Z3292953|z3292953]] 11:08, 29 September 2011 (EST)

Fragile X Syndrome – Group 5

* Introduction is perhaps a little brief. Some points that could be elaborated on are mentioned. Some referencing issues on the images in this section as well as a better explanation as to what these images actually show, why does the fragile x- chromosome look different?
* Screening could be its own heading and epidemiology could use more images.
* Etiology looks great. Good description in one of the images however the other one is not explained at all.
* Development of disease could use with some images, possibly the use of a table here could better summarize the information.
* Diagnosis could use more information aswell as some images.
* Recent research does not really contain much information, and I thought that the direction of future research could be commented on in this section also.
* Glossary needs completing. Some of the referencing web sites should be fixed up.

--[[User:Z3288196|Z3288196]] 10:42, 29 September 2011 (EST)

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
z3284061

Group 5:

References 5,6,7 & 8 refer to nothing. If all the information for a particular section refers to one reference, you don’t need to link to the same reference after each sentence. Just put it in once at the end of the paragraph, eg under screening/population testing and reference 11.

Good use of pictures especially at the beginning, maybe more in the middle? Also, maybe fix the formatting of the pictures as it disrupts the flow of the page and is distracting. Signs and diagnosis have few pictures making it look like a long trail of writing.

Well done with the glossary so far, but still some terms need to be added as it is incomplete at present.

z3332178 =]

peer review:

*dont like the picture positioning maybe space them out a bit?
*the first portion of history could be removed and just have like the x like description part, also how about a picture of the prson who discovered the disease?
*i think the screening part of epidemiology is irrelevent, it should just be who its affected and how many people suffer from the disease.
*text in aetiology is wquite verbose
*signs and symptoms is way to long, figure out a way to break all the text apart with pictures,tables etc
*little glossary and multiple references present
--[[User:Z3291423|Jasjit Walia]] 10:21, 29 September 2011 (EST)

'''Group 5'''

*intro: put the pictures on one side, will look more appealing and easier to read. Overall good info, easy to read.

*history: the little intro before the timeline is a little awkward and seems unnecessary. Maybe work on fixing this paragraph so it leads into the timeline instead of just talking about chromosomes, I found this abrupt. Timeline good.

*etiology: could be nice to have the images both on one side. It was a little confusing for the reader with the image on both sides.

*development: good section! But isn’t development and etiology the same thing? Maybe not put it as a heading but a subheading with etiology.

*diagnosis: third point FMRP antibody test can be the start of the point instead of writing a presentence to lead into it.

*signs, treatment: both great sections.

*glossary: is a little empty. Might want to include anything scientific like ‘chromosome’ as a normal person off the street might’nt know what that is. Also placing them in alphabetical order is helpful.

--[[User:Z3290558|z3290558]] 09:57, 29 September 2011 (EST)

'''Group 5 peer review'''

Introduction: It is a good overview of the different aspects of this disorder. Increasing the size of the hand drawn image will be good so that the writing can been seen clearly on the main page.

Epidemiology: The image is good and easy to understand. However, perhaps you should position the image next the text which talks about '...females are less likely to show severe signs...'. I think that genetic counseling and screening should be in a seperate management section. It would be ideal if Epidemiology contains more figures, especially if those numbers are in a some table.

Etiology: It would be better is you could explain what you mean by Xq27.3 in the text. I don't quite understand what you mean by '...given the location of the gene on a particularly fragile segment of Xq27.3...'. Although you have explained the figures in the text, it would be better if you add a one sentence summary of what each figure is displaying. This is because people might instinctively look at the figure first and not fully understand it and then read the text. Whereas if they looked at the figure and had some idea what it was showing and then read the text, the etiology of fragile x will be that much easier to understand. I like the size of the image because i can read it clearly.

Diagnosis: Please expand on the mechanisms of each technique. It would also be good to insert an image of each technique so that readers can know what the result of each technique looks like.

--[[User:Z3289301|z3289301]] 09:46, 29 September 2011 (EST)

'''Peer Assessment'''
*Introduction; well written but too brief. Need to include more information.
*Not sure if the 'screening' section is appropriate under the title 'epidemiology' especially because there is no inclusion of epidemiological data gathered from these tests but just explanations about their usage.
*I suggest using Microsoft word, power point or paint to draw the student drawings rather than from hand, especially images such as the one in the introduction showing X chromosome. Would look much more neater and professional.
*It also might be a good idea to hyperlink words in the text with the glossary. Makes it much more user friendly.
*The genetic section is well researched however the information is bit too confusing and the layout is messy. Try using tables to summarize the information.
*The section on 'development' of the gene is well written. Try and include imaged of patients at the different stages to compliment the writing.
*Try and incorporate a table in the 'signs and symptoms' section which is very text heavy.
*Diagnosis: section is a bit too brief. Not sure if this is possible but try and include images of these lab results characteristic of FXS in this section.
*Like the use of table in the 'treatment' section. Much more easier to read and understand.
*Glossary: needs to be expanded.
--[[User:Z3291622|Z3291622]] 09:38, 29 September 2011 (EST)

Be nice?
'''Group 5 evaluation'''

*The information in the introduction is good but it is way too brief. The other section of the page was not introduced or not introduced properly, like the diagnosis section. Adding these bits would probably make the introduction good and a bit more informative as to what to expect from the page. Also reference them.
*The history I think is fine the way it is.
*The epidemiology is good because you have touched upon the demography of the disease and its prevalence. It would have been better if you could add a bit more statistics on the geographical distribution of the disease, as it makes the section more credible than how it already is. Unfortunately I think the section from “Screening… “ onwards is not very relevant for this section. I would consider revising as to where this information should be placed under. I guess this section needs more research overall.
*The etiology is very informative and I think you have gone in-depth in the topic, and is well researched, but I think it needs some revision. The concepts were far too technical and it makes the reader a bit too confused about what the information is actually saying. The images are amazing, and if you could incorporate them in the text it would make the section better.
*The development of the disease section I think should be the pathogenesis of the disease. This section was not done properly, as I was expecting to see how the etiology and all the clinical manifestations relate to each other; instead it was all about the clinical manifestation. I think you need to look further into this section.
*The signs and symptoms section is very informative, but I am questioning the information as it is not referenced at all in most of the paragraph.
*Diagnosis should probably changed to diagnostic tests because the diagnosis is Fragile X. The information is good for introducing the techniques to the reader. I think further description of the tests is needed.
The treatment section has some very good information on it that describes the treatments used for the disease. It could probably be better if you could highlight the actual treatments and make it stand out.
*Recent research is a bit disappointing because the most recent research that were presented is 3 years ago. As a reader, this makes me question the content of the page, whether it is up-to-date or not. It would also be good to have a more recent paper/research and the inclusion of future direction of this disease.
--[[User:Z3290841|z3290841]] 10:24, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*The lone sentence at the beginning of the history is unnecessary.

:*Essay language such as “for example” is a bit out of place on a wiki page. Tailor language to a web page.

:*In the epidemiology section some statements are not referenced. Where are these ‘examples’ coming from?

:*Research section would benefit from the bolding of paper headings or authors names.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:13, 29 September 2011 (EST)

'''Group 5 peer Review'''
* Introduction has good information, but it needs to be more catchy for readers to want to read onto the page.
* the first line of the history section seems not to be so greatly relevant to the history section. Also in the table there’s a 30 year gap at the start of the table. No important things happened during this time?
* I don’t think the information for ‘Screening/Population testing’ is necessary to be put under the epidemiology section, rather under diagnostics.
* Explanation about the genetic location of the mutation should be given. Also information found under aetiology should be re-formatted so it is easier to read.
* The development of disease section has good information. Would it be possibly to accompany these sections with images.
* Some parts under signs and symptoms are not referenced properly as it is lacking the referencing. Also possibly include some more pics/graphs/audio/movies in this section to accompany the text.
*Diagnosis section must be expanded upon. It has potential as concepts are there but more info could be included.
* Nice use of a table in the treatments section
* the paragraph starting with: ‘’ Autism is a disorder whose etiology is not…’’ should be placed to flow with the first sentence in the recent research section. It will make the paragraph flow better.
*acronym for ‘’ Autism Diagnostic Interview (ADI-R)’’ seems bit odd, what does the R stand for?
* if possible add an article from 2011 in the recent research section to make it though you are showing the reader the most cutting edge research in this field.
*Glossary must be expanded upon, many words have not yet been included.
* In the referencing section the referencing is done well. I did notice a repetition in the referencing in reference number 37 and 38. Please fix up.
* More images are needed on the page to get the image and text ration right, especially towards the middle of the page.
*other than that good page people.

--[[User:Z3291317|Z3291317]] 08:44, 29 September 2011 (EST)

Group 5

*Introduction - ok except it was a bit hard to read with the text squeezed between the two images located left and right, maybe both images could be placed on one side, such as the right, to make it easier to read and add to the continuity and flow of the page. There is a lot that could be expanded on to add to the introduction, maybe a brief explanation of the FMR1 gene and the phenotypic manifestations as a result of it being silent.
*Etiology, not really sure but i don’t think you’ve referred to the images included here, formatting could be improved with both images being on one side
*Development of the Disease – very nice heading, information easy to follow and well referenced, best heading on this page, great job.
*Signs and Symptoms – another very well organised section
*Diagnosis – this section could be best suited to a table, making each technique easy to identify and define.
*Treatment – great use of a table, information is very clear and easy to understand.
*Glossary – more terms need to be added, such as the acronyms used throughout the page: ADHD, CGG, PCR, FXS, etc.

--[[User:Z3331469|z3331469]] 07:01, 29 September 2011 (EST)

'''Group 5 Peer Review'''

• Generally good sub-heading structure. The overall flow is consistent (nice pink tables!), however I think it could be tidied up more, for example; images placed on the right hand side of the page.

• Double up’s in references need to be removed.

• Introduction is brief and concise, good!

• Epidemiology could be improved by the addition of a table, and maybe the ‘Screening/Population testing’ section could be a sub-heading on its own.

• The first paragraph in the genetic contribution of Aetiology I feel could be worded better, but nice images and really good description of the cause of the abnormality.

• Development of the disease is a really good explanatory section, really informative! The addition of images here, would really improve it (if able to find them)

• More images needed in the signs and symptoms section. Also maybe the addition of a table to sum up the different signs and symptoms with the different age groups would help. This section seems incomplete to me, where are all your references?

• Diagnosis needs some more detail and possibly an image (for completion)

• The ‘signs and symptoms’ in the Treatment section aren’t really consistent/parallel with the ‘signs and symptoms’ section itself. This could be improved by adding a similar table in the signs and section sub-heading outlining the same ‘signs and symptoms’ (just an idea)

• Glossary needs a lot more definitions.

--[[User:Z3289829|z3289829]] 02:43, 29 September 2011 (EST)

*Intro: Like the hand drawn figure but it’s not explained and most importantly, the Image is not referenced at all. Define methylation perhaps- it’s not a good idea to have introduction with a lot of terminology because you will lose your audience if they can’t understand the initial part f the page. The description of features is brief and good way to introduce the disease, it would help if you could use an image of an affected patient instead of the chromosome (which can be sued in the etiology section)/

*History: Love the colour but perhaps add a few more events, it looks very short. You can link your bolded words to a glossary.

*Epidemiology: The “screening” section doesn’t belong here. The section explained in dot points is not referenced at all. The image is great, but there is no references to the original image or any explanation of the image itself. Genetic counselling subheading also doesn’t belong in this section.

*Etiology: Clear and easy to follow but there are words that need defining in the glossary. The section would benefit if the image of the chromosome was moved here. Perhaps more explanation on the FMR gene. The first image could do with a bit more explanation. There are words in there eg: 5UTR that are not easy to understand.

*Development of disease: Good, the subheadings help and its well-formatted. Need a picture explaining the development.

*Signs and symptoms: The image is great, you can use this as your introduction to make it a bit more engaging. You should also make it bigger and explain the distinguishing features. The research is thorough!

*Diagnosis: Very short, needs more detail.

*Treatment: Love the colour, very detailed

*Glossary: Needs a lot more work! There are many words that you will need to define. For example “ allele, permutation, asymptomatic...” list goes on.

*Reference: What’s happening in references 3-8? That’s not proper referencing format. Number 41 reference – a link isn’t a reference.

*Overall: You keep referring to the disease as either fragile X syndrome or FXS. It’s best to stick to one or the other to avoid confusion. Need more interesting images. Some excellent research but it could do with a bit of work. Good job so far.

--[[User:Z3290270|z3290270]] 02:31, 29 September 2011 (EST)

'''Group 5'''

Introduction: Good pictures but they need to be bigger. Also, this section seems like a brief summary of the sections to come. I think it would be good if you included some more general background information on fragile x.

History: This section could be longer. The table would look good with some pictures in it.

Epidemiology: Great section and I like the diagram but some of the words in the diagram are hard to read.

Genetics: This section is reasonably well explained. The genetic terms need more explaining though.

Development: Good section but needs some pictures.

Signs and symptoms: Great section. Well written, flows well and easy to understand. Needs more pictures though.

Diagnosis: This section seems a bit short. Maybe you could explain how the diagnostic techniques work.

Treatment: The table seems too text heavy. Maybe add some pictures to break up the text.

Recent research: overall, good section. --[[User:Z3291324|z3291324]] 23:23, 28 September 2011 (EST)

Group 5

Hi, I can see some progress on this page which is good, content is interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: What is FMR1 gene? Need more information here, as in when was it first discovered, some stats
#* Epidemiology: I think screening information is extensive enough to be a section on its own
#* Etiology: no explanation of FMR1 gene so far, what is its normal function? Also, please refer to images used in this section
#* Development of the disease:nice succinct, easy to follow section. Perhaps add an image for one of the stages mentioned here?
#* Signs: REFERENCING!!! But, content is good and interesting
#* Diagnosis: An image here would be nice, and an explanation of how the technology is used to diagnose FXS
#* Treatment: Nice table with good information
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to balance out the text and image ratio, some good subheadings
#Content is correctly cited and referenced.
#* poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* I feel more research needs to be done here
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#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.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* Although the content is here, there is still a lot of work needed to make this page feel complete
* glossary is very lacking in terminology
* need more images
* further research would be nice to explain this disease in more detail

--[[User:Z3291643|z3291643]] 22:56, 28 September 2011 (EST)

'''Group 5:'''

•The introduction lacks referencing and is a little short, but good use of the images to gain the attention of the reader though as I was reading it I would have preferred for the images to both be on the right hand side.

•The student drawn image on the right is not explained very well and does not contain the correct copyright information.

•Is the diagnosis section finished? It seems a little short and lacking in detail, maybe add some more information to this section, perhaps also an image to help build up this heading and make it more balanced with the other sections.

•Glossary is incomplete and should be in alphabetical order

•References are repeated, but good work on the research

•Overall I liked the formatting of the page, it is easy to read visually appealing and a good use of images to balance out the text.

--[[User:Z3332183|z3332183]] 21:28, 28 September 2011 (EST)

'''Group 5'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there and well described.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Future research is well researched, but is there any other research possibilities that are on going to show breath of research? Glossary needs to be expanded - FXS as an acronym needs to be put there. Table in treatment has too much text. Put the text outside the table and use the table to summarise the content. The information in diagnosis is too brief and could go into a table. Consider expanding that section and provide more information on how and why the techniques diagnoses FXS.

'''*Content is correctly cited and referenced.'''
File:Fragile site appearance and distribution.jpg needs to be correctly referenced. Duplication of references need to be fixed. Emotional characteristics, Language and Speech, Physical phenotype and Physical phenotype section needs references.

'''*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.'''
no explanation given for File:Fragile x chromosome..jpg. more images would be good (Eg: in Fetal Development section maybe include an image of what a fetus looks like who has FXS?)

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Decent reference list and good in-text citation but is missing referencing in some areas.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Fetal development detailed.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has followed the guidelines but some changes would be good.

--z3329495 21:17, 28 September 2011 (EST)

'''GROUP 5: Fragile X Syndrome'''
*Info in the intro is ok but could be improved by maybe including more of an explanation of the CGG codon (some may not know what a codon is and what this implicates) and a small sentence on FMR1 gene
*The placement of the two images in the introduction is a bit weird, it disrupts the end of this paragraph. Consider just putting them on the same side or putting one of them in a different section
*I don't think the first sentence of the history section is history related, looks like it could be better placed in the intro
*Timeline is ok but could possibly be researched more to include more dates, but it's good that it goes up to 2010
*I don't know if Screening/Population testing goes under epidemiology, i think it's more part of management/diagnosis
*Etiology info appears clear and concise, maybe the image of the gene would be better placed in this section
*I find the section development of disease informative and summarised well. I like the way it's structured (subheadings are fitting), an image could improve this section
*Signs and symptoms looks like its been researched extensively, info is comprehensive and summarised well, a graph or another image could improve this section and balance out the text
*Physical phenotype has no referencing (where did this info come from?)
*Diagnosis is very underdeveloped, a lot more explanation is needed for these diagnostic techniques, images could also help improve this section
*Treatment is well researched, use of a table here is suitable, however maybe you could break up the writing by splitting up the Treatment Option and Description into two different sections of the table
*Recent Research is ok, a good intro paragraph may improve this section, maybe provide more recent developments

Overall:
*Glossary is incomplete and many words need explaining, consider linking the highlighted words to the glossary as an improvement, also it might be a good idea to include acronyms in the glossary as well
*legends of images could be expanded a little more
*Reference list needs some work, I don't think links to websites are the proper way to reference

--[[User:Z3331556|z3331556]] 21:15, 28 September 2011 (EST)

'''Peer Assessment Group 5-Fragile X Syndrome'''
*The introduction contains a little bit of heavy info in it. You might want to introduce the complex concepts e.g.methylation of the CGG triplet so the reader can ease into the page.
*The absence of references in the introduction makes it feel unreliable.
*The History seems to be succinct, good work.
*Nice diagram in 'Epidemiology', however it is missing a description and copyright information
*Avoid the italics as it makes the page look inconsistent as you dont have italics very often throughout
*'Development of Disease' is divided well into distinct sub headings, easy to follow
*'Signs and Symptoms' is heavy with too much information, can you summarize some of it to condense the whole section. Also maybe consider finding some images to give it a better balance.
*'Diagnosis' requires a little more explanation of what is involved in the different types of methods.
*The table in 'Treatment' needs division of the second column maybe into treatment option and a separate description just to make it look less heavy
*'Recent Research' is structured nicely, makes it a lot easier to read
*The definitions in 'Glossary' are inadequate
*Avoid italics in the glossary
*The reference list needs some major reformatting
--[[User:Z3308968|Tahmina Lata]] 19:43, 28 September 2011 (EST)

'''Group 5: Peer Assessment'''
* Your page looks a bid 80's with all the different pinks in your table. Not a bad thing, however may be just one colour per table would be enough
* The introduction is too brief and written a little careless and lacks referencing.
* The history table is good in the way that it's chronologic and easy to read but you could write a bid more about the relevance of these events.
* Your drawing needs some copyright information and if the writing would have more contrast it would come more into account.
* The aetiology section is informative overall but some long sentences could be separated and more explanatory. Put the pictures on the same side may be to give it a bid more shape.
* The development of the disease section and signs and symptoms section read well and there is good use of subheadings.
* Is there some current research you could talk about?
* Your glossary and your references clearly need some editing and fixing up
* Overall your page seems to be written a bid careless but there are bids of interesting information in there. --z3279511 17:10, 28 September 2011 (EST)

'''Peer Assessment #5'''
*Intro looks funny with a pic on each side of the text – reconsider this formatting. Maybe both on one side and one under the other?
*Intro 1st para is very detailed for an intro- perhaps explain it more, or in more general terms. The detail will come later
*The intro sentence in history would be better in the intro.
*You keep referring to the FMR1 gene, but I have no idea what this is or how it is relevant. Please explain it somewhere! Maybe have a short para just on it and explain about it.
*In signs and symptoms, are ‘emotional characteristics’ and ‘language and speech’ meant to be their own subheadings, or subheadings of ‘intellectual development’?
*Diagnosis section is not complete, needs a lot more info and explanation of the techniques, how they work, why they are used/relevant. – Modified PCR section is too wordy.
*Treatment table is good, can you stretch it so it takes up the whole box instead of being centered? Would look better
*Recent research – surely there is more you can discuss/other areas?
*I’m sure everyone else has mentioned it, but the glossary needs work. Really, just define lots of the ‘big’ words, as you can’t assume everyone knows what they all mean.
--[[User:Z3332824|z3332824]] 11:59, 28 September 2011 (EST)

''' Group 5 Peer Assessment'''
* First student figure has no explanation as to what it's all about, and is a pretty simple diagram. What does it contain? Where is your copyright information? The same can be said with the second student-drawn figure. Make sure this is fixed!
* The introduction section appears to be pretty short. Try to keep away from using the brackets and just enter your information in a continuous format.
* The headings and subheadings work quite well. However, the lack of images in the signs and symptoms section make this difficult to read; it seems like a large block of text without anything to assist in the breakup of the page (making it difficult to read and easy for us to lose attention).
* Subheadings are used quite well. The treatment section is well presented in table format, but once again, any images to help break things up?
* The recent and future research section doesn't seem to be completed. Is there anything that can be done for the future of the disease? Is it related to any other disease processes? The glossary also seems short and isn't in alphabetic order. Please add all the terms to the glossary to ensure that there is completeness of the project! There are many terms that are difficult to understand, so slot them in here.
* There just needs to be more work done overall to ensure that the project flows smoothly and all the smaller details are accounted for. At the moment there is still a large part of the project that feels quite sketchy and requires more work.
--[[User:Z3288827|Leonard Tiong]] 10:33, 28 September 2011 (EST)

Group 5: Fragile X
*Introduction: Maybe a bit too concise, some of the content that should be in the intro is missing. Maybe this should be redone with references! Also, it doesn’t draw the reader’s attention unfortunately.
*History: Simple table, but a small explanation regarding the significance of the discoveries would be very helpful.
*Epidemiology: Nice picture, had to tilt my head a little. The “Screening/Population testing” seems like a whole new section itself. Might have to look into that?
*Etiology: This section was very well managed.
*Development: I like the subheadings, maybe an image to help add some visuals, but not required.
*Signs and Symptoms: This again, was well done, though detailed, the mass text was slightly disorientating, another image perhaps?
*Diagnosis: Looks incomplete, more info required, probably another sub-heading would do.
*Treatment: Best section in this webpage. Detailed and neatly laid out.
*Glossary: Some explanations and a few more words added here would do the trick!
*Overall: The basic fundamentals are there, some more info here, and a few tweaks there is all that is needed! Keep it up.
--[[User:Z3332327|Lisa Xiao]] 01:25, 28 September 2011 (EST)

'''Group 5'''

*Introduction should be explained a little better and also referenced
*Hand drawn image needs the correct referencing/copyright info
*Good use of subheadings in epidemiology
*Etiology is a little hard to follow
*Development of disease needs an image to break up the text
*Signs and symptoms is very text heavy- try to change it up a bit i.e. use of dot points
*Good use of table in treatment
*Glossary needs to be extended
*Overall, this has potential to be a good project with a few adjustments

'''Group 5'''

*Introduction: too much detail, give an overview. Only one of the images would be enough.

*History: well done

*Epidemiology: screening / population testing should be a separate section, very good image

*Etiology: well done,

*Development and Symptoms: both sections are clear and easy to follow, good use of subheadings

*Diagnosis: seems incomplete

*Treatment: very detailed

*Research: I would add some other examples. If you want to outline only autism, maybe change the heading.

*Glossary: there is a lot missing

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 21:31, 27 September 2011 (EST)

'''Group Peer assessment'''
*Introduction images placement may work better on one side or below the information though current placement is confusing affecting text as well.
*History requires more elaboration as well at least indication of the founder in the introduction of the history even an image of the founder would benefit this section, although the timeline is nicely done.
*Development and disease would be better as a sub heading under eitology as development of the disease links with the causation of the disease.
*Glossary needs work done as most terms are genetic related and those without a genetic background will find difficulty understanding the web page.
*Referencing only needs to adjust the links, links need to be sited properly manually.
z3332250 23:50, 26 September 2011 (EST)

Group 5 Peer Review

*Introduction does not entice the reader to read the rest of the page. Maybe less scientific language in the introduction?
*Table under history is well presented and visually appealing
*“Postnatally” and “postpubescent” need to have “development” added to the subheadings
*Well referenced
*The consistent colour scheme throughout is a nice touch
*Another image under signs and symptoms would make this section look more balanced
*Diagnosis seems brief-add information or perhaps merge with another subheading
*Glossary needs to be expanded
*Logical, clear and organised structure
*Overall, a good page. The bulk of it is there. If each section just changed some minor things, this page would improve greatly.
--[[User:Z3308965|Fleur McGregor]] 19:38, 26 September 2011 (EST)

'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it could be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

--Z3389806 07:34, 26 September 2011 (EST)

'''Group 5 Critique'''

#• Introduction should not contain clinical manifestations. It should introduce the topic as a whole. This section needs to be re-written
#• The history section is ok. The timeline could be explained a little better to give a clearer view of what the history of the disease is to the reader
#• Epidemiology should not contain the advantages and disadvantages of population testing. This should be another section in itself
#• Aetiology was fine
#• Development of the disease was ok
#• Signs and Symptoms was good
#• Diagnosis needs to be more detailed than what it is
#• Treatment and recent research is impressive
#• Glossary needs more terms added to it. It is too short, however that will be fixed when you add more explanations to the other sections and define the terms here.

--[[User:Z3289991|Robert Klein]] 18:57, 24 September 2011 (EST)

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

* I liked your page as it had a simple and easy-to-follow lay out
* Some of the images could have been made larger on your actual page just so that it adds dynamics to your page
* I was left wanting to know more about the diagnosis, this section was quite brief
* I personally found your treatment table hard to read because there was so much information. Personally I believe that maybe dot-point form could have been used to get your main points across.
* Perhaps expand upon your glossary as there were some words that weren’t in there that maybe should have been.
--[[User:Z3332629|z3332629]] 15:25, 22 September 2011 (EST)

'''Group 5 Assessment'''
*The Fragile X Chromosme. Jpg needs both an explanation and referencing.
*There is no referencing in the Introduction section. Where did you get this information from?
*History- Good idea to setup using a chart to organize the data. First time I’ve seen that.
*Fragile X Inheritance jpg looks great!!! Way to incorporate the data into a figure. However, it does still need citing.
*Not all the information in the Screening/Test Population is cited. Where is this information referenced from?
*The Development of Disease portion could use a figure or two to make it more appeasing to look at.
*Some of the information under Signs and Symptoms is also not cited. Where was this information drawn from?
*Good chart under the treatment section. However, maybe try a bullet list on the right hand column to help set the ideas apart from each other?
*The glossary link seems a little short… Are you sure there aren’t any more words which would be helpful to define for the audience?
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
*Overall, good work! Just work on the referencing and some of the visual aspects.
--[[User:Z3391078|Z3391078]] 15:09, 27 September 2011 (EST)

Group 5
* Straight into it hey- a little bit more of an “introduction” might help sorry. The first line kind of scared me. Yes it is relevant information but I think you need to almost ‘warm the reader up’ if you know what I mean. When reading anything I don’t think jumping straight into the nuts and bolts of how it works benefits anyone. I think you should start with what it is and why it is important that the reader learns about your topic
* The history section is brief and I don’t actually understand the relevance of the discoveries. While putting the information in a table shows that you know how to format it to look pretty, it is not the most effective way of showing
* Your hand drawn images still need to be referenced and copyright put on them
* Reading through I am overwhelmed by the content. This may be due to a lack of proper introduction or early explanation. I feel like the information isn’t as accessible as it could be
* Development of the disease would work well in a table I think
* Maybe put the clinical manifestations into dot points? I just feel like everything is a bulk of text and it would be better if you broke it up a little
* An image in diagnosis would help
* Treatment works well in a table
* Glossary could be extended
* You are on the right tract it is just a very heavy project. The content is all there but I found it really hard to get through.

'''Group 5'''
* Great structure with headings and subheadings, very easy to follow and read.
* Nice succinct intro. good over view of the disease. - Maybe you could dot point phenotypic abnormalities
* Some areas a little text heavy, additional pictures would fix this problem. for example some more pictures in signs and symptoms.
* Good simple history, well researched. easy to follow.
* Maybe Screening/Population testing could be its own heading.
* Great section on development of disease! I like the format very interesting relevant information! well done!
* Treatment section well put together but a little text heavy- try condensing info or bullet points.
* Make sure all the pictures are referenced properly.
* Nice to see your references grouped.
* NIce student drawn picture.
* Make sure all your acronyms/ scientific lingo is in the glossary.
* I liked that you has a continuous colour scheme for your tables. It makes your page look very neat.
* The bottom of the page is a little text heavy.

*'''Introduction''': Concise and to the point.
*'''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.
*'''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.
*'''Screening/Population testing''': Looks fine.
*'''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.
*'''Development''': Well explained, good use of subheadings.
*'''Signs and Symptoms''': Also well explained, good use of subheadings.
*'''Diagnosis''': Too short. What about non-genetic diagnosis?
*'''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?
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?
*'''Glossary''': Too short, more terms need to be explained.
*'''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.
*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?

'''Group Project 5'''

*The introduction was too in detail and did not seem like an introduction. Also there are no references ?
*the history is easy to read
*Etiology - very nice section of information
*Development of the Disease - was a good idea to put this in and the information is easy to read, maybe include some hyperlinks to the glossary?
*The treatment table is quite informative and easy to read due to its structure and quite appealing to the eyes
*More should be added to the glossary

--[[User:Z3330313|z3330313]] 20:02, 28 September 2011 (EST)

'''Peer Assessment: Group Project 5'''
*The introduction has no references.
*More pictures in the sections on development, signs and symptoms and diagnosis would help to make the written work easier to follow. Examples of pictures that could be added are images of neural crest development put in the development section or images of diagnostic techniques in the section on diagnosis.
*The section on treatment is clear and informative.
*The different diagnostic procedures could be explained more, such as how they are each conducted.
*Instead of having the uncommon words highlighted in bold, maybe you could link the words to their definition down in the glossary section.
*Some of the references are duplicated. They can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
*In conclusion, this project is both accessible to people who have no great scientific knowledge, but also delves into quite specific knowledge. A good balance.
--[[User:Z3217345|z3217345]] 21:59, 27 September 2011 (EST)

'''Peer Review'''

* the layout was not well structured
* was able to understand the disorder

--[[User:Z3060621|z3060621]] 21:31, 28 September 2011 (EST)

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{{2011GroupDiscussionMH}}

=='''Discussion'''==

Hey,
I'm under the impression that he is closing it tomorrow at 5pm.
Also, make sure you aren't editing stuff out. (Tara, im looking at you :P you edited out some of my stuff, but it's all good).
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

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'''BORIS!'''
This is what you missed in todays lab: you need to read through the peer review comments and work on the comments that are applicable to your section (although you don't have to agree with all the comments), it is also now time to work on all the sections together and we still need more pictures (make sure they are referenced properly and include the student template - if we have any material not cited properly, Mark is going to delete it), we also need to look into maybe adding videos to our page and Sandra would like us all to contribute to the recent research section. We have 2 weeks to finalise our wiki and our page will be closed at 11am two Thursdays from now. Thanks!

--[[User:Z3290815|Tara Lofthouse]] 19:13, 29 September 2011 (EST)

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Collins SC, Coffee B, Benke PJ, Berry-Kravis E, Gilbert F, et al. (2010) Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype. PLoS ONE 5(3): e9476. doi:10.1371/journal.pone.0009476

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Nice work Sandra! I will keep looking and i see you changed your table to pink too haha --[[User:Z3290815|Tara Lofthouse]] 20:54, 18 September 2011 (EST)

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Hey guys, i have just edited our group page and put up 3 pictures! Please try to find more before Monday (especially under development of the disease and signs and symptoms as these parts are so dense with writing and thus need pictures to break it up a little bit)! Cheers, --[[User:Z3290808|Sandra Issa]] 00:24, 18 September 2011 (EST)

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Here:

http://3.bp.blogspot.com/-88xXtruHpyo/TlaALBe6CaI/AAAAAAAABx8/ZMdZULFKEns/s1600/happy%2Bcamper.jpg

{|
|-
| Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)
| 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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.
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.
Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients). Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.”
|-
| Treatment of Mood Instability and Aggression
| 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.
Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”
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.”

|}

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Hey guys, yep i will be there at 10 count me in! --[[User:Z3290808|z3290808]] 09:42, 15 September 2011 (EST)

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It looks like it is going to be late nights all round. We should try and pump out an intro in that time tomorrow as well as at least one image? --[[User:Z3290815|Tara Lofthouse]] 18:52, 14 September 2011 (EST)

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Okay, Tomorrow at 10am it is. I'll finish my stuff off tonight (it looks like being a late night :P).
I'm assuming that it doesn't have to be perfect by tomorrow. It just needs to look alright, so that people can give us feedback before we finish it, yeah?
Also, Boris, Interview is on the 27th. I was just visiting a friend. I'll tell you how it goes though, when it does happen. --[[User:Z3290618|Ziggy Harrison-Tikisci]] 17:43, 14 September 2011 (EST)
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I can make it at 10am on Thursday as well --[[User:Z3290815|Tara Lofthouse]] 12:08, 14 September 2011 (EST)

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Ooo, interview? How'd it go?
I don't have time to meet up today (Wednesday), but I can see you guys in the lab at 10 tomorrow, before the class.
--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)

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Hey Guys, Sorry I've been in Melbourne for the week, so haven't done any work. Getting on it now. Going to do all my referencing, editing etc.
Wanted to ask if there is a time when we can get together, go through it all and make it pretty. Did we just want to do this before our lab on thursday, or if you guys have some time on wednesday afternoon?
Furthermore, how harsh is the criticism/feedback? Doesn't mince his words, does he? --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:51, 12 September 2011 (EST)

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Hey Boris yes i am experiencing the same problem. I cannot see the references and the reference list looks like a bunch of arrows facing superiorly. I got a bit worried but then checked the other groups and they had the same issue. I'm not sure what we can do? Let me know. ---[[User:Z3290808|Sandra Issa]] 09:49, 9 September 2011 (EST)

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WHAT HAPPENED TO OUR REFERENCES. Can you guys do me a favour and tell me if you can see them? I was trying to put in an image just then and when I did the save it came up with references wiped. I tried undoing my last edit to no avail. There are still 30 something references, there's just nothing IN them. When I finished my word edit earlier today I actually saved the ENTIRE script as a word document; when I tried to rewrite EVERYTHING with that same (working) script it still came up with stuffed up references.

Let me know if you guys see the same problem. If you do, I'll have to get in contact with Mark Hill to fix the script.
--[[User:Z3290689|Boris Zolotarev]] 23:31, 8 September 2011 (EST)

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I hate how the times shown on the editing thing are totally out of whack....can I post anything up at the moment? ><
--[[User:Z3290689|Boris Zolotarev]] 23:27, 7 September 2011 (EST)

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Hey guys, i have just added the diagnosis part of our page and have also finished the treatment. Let me know if you think the treatment is too long? Or if you want to make any changes to the "Recent Research" part of our page.

Also, i will add in more references for this part very soon. I have put in a general reference (review article) but will make sure i include all references used very soon.

Have a good night, --[[User:Z3290808|Sandra Issa]] 21:16, 7 September 2011 (EST)

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Suggestion: rename '''Development of disease''' to '''Progression of disease'''. Also, I should have a heap up later tonight, I'm compiling it all in a separate document at the moment.

--[[User:Z3290689|Boris Zolotarev]] 15:39, 7 September 2011 (EST)

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Hey guys, just letting you know that i have found a great article which addresses many current 'treatments' for FXS. Also, i have found another article which summarises the current methods of diagnosing FXS. I will add this information (what i think is most relevant from the articles) onto our group page under the headings "treatment" and "diagnosis" '''very soon'''. Please feel free to add in anything that you believe i have not addressed under these headings. Also, i will try to edit our page as a whole soon so that it looks more uniform in appearance. Over the next couple of days we should all read each of the sections and try to add in additional information that someone else may have missed. Also, a reminder to keep an eye out for relevant pictures that have unrestricted access to add onto our page!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:32, 5 September 2011 (EST)

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Hey, I'm doing a whole bunch now. I'll properly reference it all later, but I'm getting a lot of it off the american National Institute of Health. They've got references for all of it. So when I have more time, I'll go through those references, add them, and edit the information. So, what I put on the group page will just be an overview. Also, you people should go to bed earlier :)
http://www.nichd.nih.gov/publications/pubs/fragileX/sub6.cfm
--[[User:Z3290618|z3290618]] 09:49, 1 September 2011 (EST)

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z3290808: I don't know why it wouldn't let you save, i wasn't editing at that time. Try again and if it doesn't work maybe paste your work here with your references and one of us can put it onto the project page for you?

Boris: At least something is up :) My section needs a lot more editing and a lot more cross checking with other references as well.. Any progress is good progress at the moment
--[[User:Z3290815|Tara Lofthouse]] 03:35, 1 September 2011 (EST)

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Heya, I took a stab at my section but I'm a bit dead at the moment '''(points to timestamp)'''. I'll try get some more done tomorrow between the lecture and lab.

On the plus side, I added another 6 or 7 references to our thingy ^^

--[[User:Z3290689|Boris Zolotarev]] 01:28, 1 September 2011 (EST)

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Guys it's not letting me save what i have written onto the group page! Is anyone currently on and trying to edit at this same time?
--[[User:Z3290808|z3290808]] 22:41, 31 August 2011 (EST)

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Yo Boris, You do Etiology, I'll do signs and symptoms. We can work towards the middle.
That leaves history and epidemiology to Tara and Recent research to Sandra. And then we can all refine it/make an intro.
We can at least do that to start with.
Also: can everyone contribute to the glossary. If you find any terms that people (eg. me) wont understand, please keep them.--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:10, 25 August 2011 (EST)

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The only reason why we need to put our names down now is to satisfy the weekly individual assessment but of course we can change things. Just put your name down for epidemiology or whatever was left over and we'll discuss it tomorrow. Maybe if we could get to the lab 10-15min earlier because we never get enough time at the end of the lab?

--[[User:Z3290815|Tara Lofthouse]] 19:50, 24 August 2011 (EST)

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Just skimmed through this (damn I left it late >< ), should I nominate something now or should we discuss it tomorrow?
Also, what do you guys think of having some sort of realtime chat method? Facebook or something of the sort...
--[[User:Z3290689|Boris Zolotarev]] 19:17, 24 August 2011 (EST)

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Yeah i know but the ones i put my name down for are really not that lengthy. We definitely need to have a chat tomorrow.
--[[User:Z3290815|Tara Lofthouse]] 17:45, 24 August 2011 (EST)

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Hey guys, you haven't left much for Boris and i to do lol .. I don't mind doing the recent research part - focussing on autism and fragile x.. but then i don't know what Boris would do? I will sign my name for now but i think we will have to change it around a little to better make the work load equally spread.

Cheers, --[[User:Z3290808|Sandra Issa]] 16:17, 24 August 2011 (EST)

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I've taken it all on board and changed it. I'm fine for you to do whatever you want but doing both the genetic component and the signs and symptoms might be a lot of work. As long as everything is spread evenly i don't mind :)

--[[User:Z3290815|Tara Lofthouse]] 16:35, 23 August 2011 (EST)

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Hey, I was wondering if anyone minds if I do 'Genetic contribution'. Also, is it okay if I follow the timeline of the disease? I will start with the chromosome, saying what the defect causes at a molecular level, and then when it first presents, and how it affects the development etc up until how it presents in the adult. Which means I'd probably do "Signs and symptoms (clinical Presentation)" as well.
ALSO, we need to do a brief history of the disorder. So, below I've just tweaked the layout Tara and Sandra put up: let me know what you think

* Introduction
* History of Disease
* Epidemiology
* Etiology
** Genetic contribution
* Development of Disease
** Fetal Development
** At birth
** In Adult
*** Signs and symptoms
* Recent research
** Fragile X and Autism
** Diagnosis
** Treatment
--[[User:Z3290618|z3290618]] 15:18, 23 August 2011 (EST)

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Yeah, i think it makes sense how you've got it Sandra. However like Boris said maybe instead of having the heading "Autism and Fragile X Syndrome" maybe we could have recent research/current studies or something along those lines and include it there along with diagnosis and treatment? Do you think that etiology is too similar to genetic contribution?

ALSO!!!
What headings would you like to research? I set up a "Who's doing what?" heading on this page to sign your name next to.

--[[User:Z3290815|Tara Lofthouse]] 12:39, 23 August 2011 (EST)

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Hey guys, i have come up with a couple of headings that we can use:

* Introduction (short summary)
* Epidemiology
* Signs and Symptoms (Clinical Presentation)
* Etiology
* Genetic Contribution
* Autism and Fragile X syndrome
* Diagnosis?
* Treatment?
* References

Tara i also like the format that you have included below.. i basically have made something similar but in different order based on what i think should come first perhaps? The ones with a question mark beside them are ones that i am unsure if we should include or not. Let me know what you think!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:03, 23 August 2011 (EST)

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Hahaha of course it's your place to say so.. good suggestion, i'll fix it up now and if we want to change it again than that's no problem. I just thought i'd put something up to get started and we can go from there. What i've done is no where near completed.
--[[User:Z3290815|Tara Lofthouse]] 18:52, 22 August 2011 (EST)

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(I know it's not my place to say so before I've submitted my own suggestion but) I think I'd put "Autism and Fragile X Syndrome" within the "recent research" subtopic. I'll put up a suggestion by tomorrow evening, if not earlier.
--[[User:Z3290689|Boris Zolotarev]] 09:27, 22 August 2011 (EST)

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'''Hello everyone,''' what do you think about using the following headings for our project? Are there ones that you think we could omit or ones that you would like to add? We also need to decide on who is doing what.
* Signs and symptoms
* Diagnosis
* Genetics
* Etiology
* Epidemiology
* Treatment
* Recent research
** Autism and Fragile X Syndrome
* References

--[[User:Z3290815|Tara Lofthouse]] 16:26, 21 August 2011 (EST)

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[http://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Lab_2_-_Group_Project Group project] --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:58, 4 August 2011 (EST)

[http://www.ncbi.nlm.nih.gov/omim OMIM]--[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:59, 4 August 2011 (EST)

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Here's another interesting topic.

[http://en.wikipedia.org/wiki/Apert_syndrome Apert Syndrome aka acrocephalosyndactyly] --[[User:Z3290689|z3290689]] 11:38, 11 August 2011 (EST)

=='''Congenital Hypomyelinating Neuropathy'''==

What do you guys think you of this topic [http://omim.org/entry/605253 Congenital Hypomyelinating Neuropathy]?

There are quite a few articles on it:

Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination.

Analysis of congenital hypomyelinating Egr2 Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination.

P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves.

Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg–Hirschsprung disease: Phenotypes linked by SOX10 mutation.

A lot of them overlap with their findings and the focus of their studies, so it seems to be a pretty thorough topic.

--[[User:Z3290689|Boris Zolotarev]] 21:03, 7 August 2011 (EST)

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I’m all for doing '''Congenital Hypomyelinating Neuropathy''' as our topic.

Here are some articles I have found:

'''Research Articles:'''

[http://neuro.cjb.net/content/29/8/2312.full.pdf+html Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure in Mice Carrying the Egr2 I268N Mutation]

* 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

[http://jnnp.bmj.com/content/48/12/1269.full.pdf Congenital hypomyelinating neuropathy]

* 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:'''

[http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TBD-3W37BMX-C-1&_cdi=5140&_user=1975841&_pii=S0887899498001386&_origin=&_coverDate=03%2F31%2F1999&_sk=999799996&view=c&wchp=dGLzVzb-zSkWA&md5=d2e9e64dfc821d71ec81675f01932b8a&ie=/sdarticle.pdf Congenital hypomyelinating neuropathy: two patients with long-term follow-up]

* 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

--[[User:Z3290815|Tara Lofthouse]] 12:22, 9 August 2011 (EST)

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=='''Fragile X Syndrome'''==

==='''Articles'''===

Hey guys,
I had a look at Congenital Hypomyelinating Neuropathy and to be honest i did not find it very appealing. I found the disorder "Fragile X Syndrome" to be very interesting! Can you guys please check out the following link on [http://www.fragilex.org/html/cause.htm/ Fragile X Syndrome] and let me know if the disease also interests you!? I found the information on it is quite extensive and the disease is well known. If you do not want to base our project on this syndrome, i am sure we can decide on one we can all enjoy studying! :)

Here are some interesting articles that i have found on '''Fragile X Syndrome''':

* '''Review Article''': Fragile X syndrome: from gene discovery to therapy <ref><pubmed>21196228</pubmed></ref>

- This review focuses on the molecular and biochemical pathways shown to be relevant in the Fragile X Syndrome. It describes that a mutation in the FMR-1 gene was found to lead to Fragile X Syndrome due to excessive repeats of the trinucleotide sequence CGG which is known to inactivate the FMR-1 gene, making the X chromosome fragile and prone to breakage. This review article also demonstrates the many vital functions of the FMR-1 gene such as its role in RNA transport and stability, thus absence of the protein transcribed and translated from this gene is thought to affect brain development and thus leads to signs of mental retardation.

* '''Research Article:''' DNA methylation represses FMR-1 transcription in fragile X syndrome <ref><pubmed>1301913</pubmed></ref>

- This research article explores the two molecular differences of the FMR-1 gene in normal individuals vs. those with Fragile X Syndrome. These differences are an increase in size of an FMR-1 exon containing a CGG repeat and abnormal methylation of a CpG island 250 bp proximal to this repeat. This research article also shows how these two abnormalities repress transcription of the FMR-1 gene, leading to the absence of the FMR-1 protein which is thought to be the contributing factor to the Fragile X phenotype.

--[[User:Z3290808|Sandra Issa]] 19:53, 9 August 2011 (EST)

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Here are some articles I have found for '''Fragile X syndrome''':

'''Research Article:''' The state of synapses in Fragile X Syndrome <ref><pubmed>19325170</pubmed></ref>

* Fragile X Syndrome is the most common inherited form of mental retardation and a leading genetic cause of autism.

* Evidence that suggests alterations in synapse number, structure and function are associated and contribute to both Fragile X Sydrome and autism.

* Fraile X Syndrome is caused by loss of function of the Fmr1 gene which encodes the RNA binding protein, FMRP (FMRP is present at synapses where it associates with mRNA and polyribosomes).

* FMRP is also has a role in synapse development, elimination and plasticity.

* An understanding of the molecular and synaptic function of FMRP, as well as the consequences of its loss, has led to the early developments of therapeutic strategies for Fragile X Syndrome.

'''Research Article:''' Fragile x syndrome: history, diagnosis, and treatment. <ref><pubmed>6348096</pubmed></ref>

'''Review Article:''' Systematic review of pharmacological treatments in fragile X syndrome <ref><pubmed>19822023</pubmed></ref>

'''Review Article:''' FMR1 and the fragile X syndrome: human genome epidemiology review <ref><pubmed>11545690</pubmed></ref>

--[[User:Z3290815|Tara Lofthouse]] 14:37, 16 August 2011 (EST)

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==='''Images'''===

[[File:FMR4 is silenced in fragile X syndrome.jpg|thumb|FMR4 is silenced in fragile X syndrome]]

[[File:FMR4 is silenced in fragile X syndrome.jpg|350px]]

File:FMR4 is silenced in fragile X syndrome

--[[User:Z3290808|Sandra Issa]] 10:20, 14 August 2011 (EST)

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[[File:Hippocampal_Formation.jpg‎|thumb|Hippocampal_Formation]]

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

File: Hippocampal_Formation

--[[User:Z3290815|Tara Lofthouse]] 13:49, 17 August 2011 (EST)

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Like?
[[File:Fragile site appearance and distribution.png|300px]]
File: Fragile site appearance and distribution
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 08:55, 18 August 2011 (EST)

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[[File:Journal.pone.0013559.g001.png‎|thumb|FXR1 (A) and FXR2 (B) crystal structures]]

[[File:Journal.pone.0013559.g001.png‎|300px]]

File: FXR1 and FXR2 crystal structures

--[[User:Z3290689|Boris Zolotarev]] 11:00, 18 August 2011 (EST)

== '''Who's doing what?''' ==

* Introduction = DO AT THE END!!!!
* History of Disease = Tara
* Epidemiology = Tara
* Etiology = Boris
** Genetic contribution<ref>http://www.fragilex.org/html/premutation.htm</ref><ref><pubmed>10208170</pubmed></ref><ref><pubmed>11445641</pubmed></ref><ref><pubmed>12638084</pubmed></ref><ref>http://ghr.nlm.nih.gov/condition/fragile-x-syndrome</ref><ref><pubmed>8348153</pubmed></ref>
** Development of Disease
*** Fetal Development
*** At birth
*** In Adult
* Signs and symptoms = Ziggy
** Physical phenotype
** Social interaction
**Intellectual development
* Recent research = Sandra
** Fragile X and Autism
** Diagnosis
** Treatment
* References

==ZIGGY'S STUFF==
Just leaving this here for the next hour, so that I don't have to retype it all (can't get wifi in the embryo lab).

The hallmark of the fragile X syndrome is mental retardation, which was noted as early as 1943 in a report of a large family with 11 mentally retarded males and two mildly retarded females. 64 The clinical phenotype associated with the syndrome has since been widened to include a variety of cognitive, physical, and behavioral characteristics (reviewed in Mazzocco). 65 Almost all males with the full mutation exhibit some clinical features of the fragile X syndrome. Also, most affected males do not reproduce, presumably due to the severity of mental retardation. With regard to cognitive function, affected males often exhibit developmental delay very early in childhood. By the age of 3 years, most males will test in the mentally retarded range. 66 Ultimately, almost all males with the fragile X syndrome are mentally retarded, with severity ranging from profound (IQ <20) to mild mental retardation (IQ 50–70), with most being moderately retarded (IQ 40–54) (reviewed in Hagerman). 67 Physically, adult males often have a long narrow face, prominent ears, a prominent jaw, and macroorchidism (reviewed in Hagerman). 67 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, and mitral valve prolapse (reviewed in Warren and Sherman). 8 Males with the fragile X syndrome also tend to exhibit behavioral features such as hyperactivity, social anxiety, perseverative speech and language, tactile defensiveness, stereotypies (e.g., hand-flapping), and hand biting (reviewed in Hagerman). 67 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. 68 The association of fragile X with autism, however, is not clear because the proportion of males with the fragile X syndrome meeting the diagnostic criteria for autism seems to diminish with age. 68

Physical phenotype
Before puberty, children with Fragile-X tend to have no discernable 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. 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 macro-orchidism: enlargement of the testicles. Fragile-X patients may also have loose connective-tissues, allowing their joints to be more flexible that normal. This may cause complications arising from increased risk of 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.

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. Their anxiety often manifests itself as discontinuous speech and a lack of eye contact.

Results indicate that compared to the control group, individuals with FXS exhibited decreased activation of prefrontal regions associated with complex social cognition, including the medial and superior frontal cortex, during successful face encoding. Further, the FXS and control groups showed significantly different relationships between measures of social anxiety (including gaze-fixation) and brain activity during face encoding. These data indicate that social anxiety in FXS may be related to the inability to successfully recruit higher level social cognition regions during the initial phases of memory formation.
Reference: Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome.

Intellectual development
As a generalisation, the majority of Fragile-X patients have an IQ between 1 and 2 standard deviations below the population mean. This equates to around 40-85. Few Patients lie out-side this range, with approximately 20% within the ‘normal’ range (85-115) and less below 40. Females however, show lower impairment, with only one-third having IQs within the ‘mental retardation’ range.
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.
Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points.

Studies of intellectual function in FXS often demonstrate a mean IQ decline of 4 to 9 standardized points over intervals ranging from several months to 13 years.
Reference: Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Working Memory
First, when individuals affected by the premutation are examined as a group, they exhibit a weakness only for tasks that reflect functioning of the central executive subcomponent of working memory.

Second, when both permutation sub-groups are examined together, the extent of the central executive deficit is significantly correlated with larger CGG repeat expansions.

For permutation males who are asymptomatic, mild executive dysregulation, inhibitory deficits that worsen with age, and declarative verbal learning and memory are notable.

The detection of a deficit in the central executive component of working memory in the fourth decade of life that progressively deteriorates with age suggests a cumulative process that may be a cognitive correlate to the underlying degenerative process identified in premutation males.

The significant correlation between CGG repeat length and central executive working memory in asymptomatic carrier males suggests greater neuropathology in carrier males with larger expansions in FMR1 mRNA transcripts.
Reference: Lifespan changes in working memory in fragile X premutation males

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.

== '''References''' ==
<references/>

2011 Group Project 5

2011-10-12T04:46:27Z

Z3290618:

{{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 [[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''asymptomatic''']], studies have shown that it predisposes to Parkinson's disease, intention tremor and brain [[#Glossary | '''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 [[#Glossary | '''methylation''']] of the CpG island that typically regulates its [[#Glossary | '''expression''']], the loss of which inhibits the binding of [[#Glossary | '''transcription factors''']], effectively [[#Glossary | '''silencing''']] the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. [[#Glossary | '''Transcription''']] is similarly inhibited by [[#Glossary | '''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 fetal 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><pubmed>9421410</pubmed></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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>. [http://www.fragilex.org/html/adhd.htm ADHD and a short attention span] are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks<ref>http://www.fragilex.org/html/adhd.htm</ref>.

===== 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub9.cfm</ref>.
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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>. 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<ref>http://www.nichd.nih.gov/publications/pubs/fragileX/sub10.cfm</ref>.
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<ref>http://www.fragilex.org/html/speech.htm</ref>.

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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= 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><pubmed>9421410</pubmed></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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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. ADHD and a short attention span are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks.

===== 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/>

----

{{2011Projects}}

2011 Group Project 5

2011-10-12T04:28:44Z

Z3290618: /* Behavioural characteristics */

{{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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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. ADHD and a short attention span are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks.

===== 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/>

----

{{2011Projects}}

2011 Group Project 5

2011-10-12T04:27:23Z

Z3290618: /* Signs and Symptoms */

{{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.

=== Behavioural characteristics ===
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur. For information on these see [http://www.nichd.nih.gov/publications/pubs/fragileX/index.cfm National Institute of Child Health & Human Development] and [http://www.fragilex.org/html/home.shtml The National Fragile X Foundation].

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. ADHD and a short attention span are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks.

===== 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/>

----

{{2011Projects}}

2011 Group Project 5

2011-10-12T04:18:20Z

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= 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.

===== Behavioural characteristics ======
There are a number of of phenotypic behavioural characteristics associated with Fragile-X syndrome. It is important to note that a number of these are purely observational. Many do not have scientific studies associated with proof of the characteristic nor explanations of by which mechanism they occur.

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. ADHD and a short attention span are associated with Fragile-X patients. Girls are less likely to be diagnosed with hyperactivity, however, they do tend to exhibit an inattentiveness and a failure to focus on long, difficult tasks.

===== 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/>

----

{{2011Projects}}

Talk:2011 Group Project 5

2011-10-12T04:02:25Z

Z3290618:

{{2011GroupDiscussionMH}}
Just in case you guys couldn't find it!
--[[User:Z3290815|Tara Lofthouse]] 14:31, 11 October 2011 (EST)

===The final stretch!===

* The group projects will be locked after next weeks practical ('''5:00 pm''') for no further changes.
* You are free to make any changes you wish to the existing project page (additions, deletions, formatting etc).
* You should also go through all displayed uploaded files and make sure they conform to the information requirements I specified in today's practical (without the numbering):
# Correct image file name (describes what the image shows, keep it brief and to the point).
# Original legend information and any clarifying description that shows how it relates to your group topic.
# Correct citation format in its own "Reference" sub-sub-heading (if pubmed extension does not format correctly paste the entire text in and add a PMID number link at the end) You can also link to any other location of this citation, but this is not a requirement.
# The copyright information (Don't just paste, make sure it says that you can use then image).
# Finally include the student image template (copy the following in read mode, and paste in your image information in edit mode) <nowiki>{{Template:2011 Student Image}}</nowiki>

* You should complete all your updates ASAP and not leave everything to the last practical class where you will have limited time.
* We have a guest presenter for next week practical and '''I do not want any Group work during her part of the practical'''.
** Remember all edits are logged and time-stamped, I can see who has been editing when they should doing the practical.

===Last Addition to your Project Page===

* Is a new sub-heading entitled "Related Links".
* This sub-section should link to other pages on the embryology website that relate to your topic.
* Format as a bullet list, link first and a brief description (one line) of how it relates to the topic.
* An example is shown below.

==Related Links==

* [[Placodes]] - this page relates to today's practical as the earliest sensory specialisation visible on the embryo surface during week 4.

----

Hey guys, i have added some more recent/ future research into the corresponding heading! I have also added another picture under this heading. The research is very current (2011) which is good. Hope you guys like it :) --[[User:Z3290808|z3290808]] 13:37, 8 October 2011 (EST)

=== Sandra ===

SAAAAAAAAANDRA:

This is what it will look like: [[Week 2|this is how you make a link to a page on this website thingy bla]]

This is what you type in: <nowiki>[[Week 2|this is how you make a link to a page on this website thingy bla]]</nowiki>
* Where you're linking it from "Week 2"
* Description "this is how you...."

--[[User:Z3290689|z3290689]] 12:45, 6 October 2011 (EST)
----

==='''Discussion 2'''===

Hey, I'll be doing quite a few edits today/tonight. I'm putting up all of my references now.
Also, I'm going to be making sure all of our referencing is in the same format. I noticed there are a few that link the website for an article. I'll try to fix them up.
I want to just check with you guys if the following is okay:
I need to put on my student page what my contribution to the group project is. I'm going to put up "signs and symptoms" without the two pictures. The picture I put in the discussion in the first weeks (though someone else put it in the actual page) and finally the formatting for the tables (but in grey-scale as it was originally). Are there any objections for to that?
Let me know if there is anything else, and make sure you aren't accidentally editing out my edits if we're doing work :D
--[[User:Z3290618|Ziggy Harrison-Tikisci]]

Hey guys, i have edited my diagnosis section - i have put it in a table and have found some relevant videos. Also, i will try to find some more recent research. It would be great if everyone can also pitch in to this section anytime you find some recent research that is relevant to our topic but not addressed in one of the subheadings.
To Ziggy - could you please finish off the referencing for your section Signs and Symptoms. Also if possibly, could you please add a photo to the group page. That would be much appreciated.
Cheers, --[[User:Z3290808|z3290808]] 11:59, 6 October 2011 (EST)

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_5_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_5_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

[[2011_Group_Project_5|'''Group 5''']]: [[User:z3290618]] | [[User:z3290689]] | [[User:z3290808]] | [[User:z3290815]]

----

=='''PEER REVIEW COMMENTS'''==

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
--[[User:Z3284061|z3284061]] 11:54, 29 September 2011 (EST)

'''Group 5'''

* The images might be better all on the same side
* An image is needed in Development
* "Signs and Symptoms" is a little text heavy and needs more references
* Diagnosis appears to be incomplete
* Glossary needs to be expanded
* Links to the glossary might be helpful
* Double referencing needs to be fixed
--[[User:Z3292953|z3292953]] 11:08, 29 September 2011 (EST)

Fragile X Syndrome – Group 5

* Introduction is perhaps a little brief. Some points that could be elaborated on are mentioned. Some referencing issues on the images in this section as well as a better explanation as to what these images actually show, why does the fragile x- chromosome look different?
* Screening could be its own heading and epidemiology could use more images.
* Etiology looks great. Good description in one of the images however the other one is not explained at all.
* Development of disease could use with some images, possibly the use of a table here could better summarize the information.
* Diagnosis could use more information aswell as some images.
* Recent research does not really contain much information, and I thought that the direction of future research could be commented on in this section also.
* Glossary needs completing. Some of the referencing web sites should be fixed up.

--[[User:Z3288196|Z3288196]] 10:42, 29 September 2011 (EST)

Group 5:
Overall, Great work on the page:
*The image in Epidemiology section needs a description and the copyright information. Also, the number of references is the same.
*in the Signs and symptoms, more pictures would make it more interesting. Some of the paragraphs like Physical Phenotype needs to be references.
* A reformatting is needed in the References instead of listing the websites.
z3284061

Group 5:

References 5,6,7 & 8 refer to nothing. If all the information for a particular section refers to one reference, you don’t need to link to the same reference after each sentence. Just put it in once at the end of the paragraph, eg under screening/population testing and reference 11.

Good use of pictures especially at the beginning, maybe more in the middle? Also, maybe fix the formatting of the pictures as it disrupts the flow of the page and is distracting. Signs and diagnosis have few pictures making it look like a long trail of writing.

Well done with the glossary so far, but still some terms need to be added as it is incomplete at present.

z3332178 =]

peer review:

*dont like the picture positioning maybe space them out a bit?
*the first portion of history could be removed and just have like the x like description part, also how about a picture of the prson who discovered the disease?
*i think the screening part of epidemiology is irrelevent, it should just be who its affected and how many people suffer from the disease.
*text in aetiology is wquite verbose
*signs and symptoms is way to long, figure out a way to break all the text apart with pictures,tables etc
*little glossary and multiple references present
--[[User:Z3291423|Jasjit Walia]] 10:21, 29 September 2011 (EST)

'''Group 5'''

*intro: put the pictures on one side, will look more appealing and easier to read. Overall good info, easy to read.

*history: the little intro before the timeline is a little awkward and seems unnecessary. Maybe work on fixing this paragraph so it leads into the timeline instead of just talking about chromosomes, I found this abrupt. Timeline good.

*etiology: could be nice to have the images both on one side. It was a little confusing for the reader with the image on both sides.

*development: good section! But isn’t development and etiology the same thing? Maybe not put it as a heading but a subheading with etiology.

*diagnosis: third point FMRP antibody test can be the start of the point instead of writing a presentence to lead into it.

*signs, treatment: both great sections.

*glossary: is a little empty. Might want to include anything scientific like ‘chromosome’ as a normal person off the street might’nt know what that is. Also placing them in alphabetical order is helpful.

--[[User:Z3290558|z3290558]] 09:57, 29 September 2011 (EST)

'''Group 5 peer review'''

Introduction: It is a good overview of the different aspects of this disorder. Increasing the size of the hand drawn image will be good so that the writing can been seen clearly on the main page.

Epidemiology: The image is good and easy to understand. However, perhaps you should position the image next the text which talks about '...females are less likely to show severe signs...'. I think that genetic counseling and screening should be in a seperate management section. It would be ideal if Epidemiology contains more figures, especially if those numbers are in a some table.

Etiology: It would be better is you could explain what you mean by Xq27.3 in the text. I don't quite understand what you mean by '...given the location of the gene on a particularly fragile segment of Xq27.3...'. Although you have explained the figures in the text, it would be better if you add a one sentence summary of what each figure is displaying. This is because people might instinctively look at the figure first and not fully understand it and then read the text. Whereas if they looked at the figure and had some idea what it was showing and then read the text, the etiology of fragile x will be that much easier to understand. I like the size of the image because i can read it clearly.

Diagnosis: Please expand on the mechanisms of each technique. It would also be good to insert an image of each technique so that readers can know what the result of each technique looks like.

--[[User:Z3289301|z3289301]] 09:46, 29 September 2011 (EST)

'''Peer Assessment'''
*Introduction; well written but too brief. Need to include more information.
*Not sure if the 'screening' section is appropriate under the title 'epidemiology' especially because there is no inclusion of epidemiological data gathered from these tests but just explanations about their usage.
*I suggest using Microsoft word, power point or paint to draw the student drawings rather than from hand, especially images such as the one in the introduction showing X chromosome. Would look much more neater and professional.
*It also might be a good idea to hyperlink words in the text with the glossary. Makes it much more user friendly.
*The genetic section is well researched however the information is bit too confusing and the layout is messy. Try using tables to summarize the information.
*The section on 'development' of the gene is well written. Try and include imaged of patients at the different stages to compliment the writing.
*Try and incorporate a table in the 'signs and symptoms' section which is very text heavy.
*Diagnosis: section is a bit too brief. Not sure if this is possible but try and include images of these lab results characteristic of FXS in this section.
*Like the use of table in the 'treatment' section. Much more easier to read and understand.
*Glossary: needs to be expanded.
--[[User:Z3291622|Z3291622]] 09:38, 29 September 2011 (EST)

Be nice?
'''Group 5 evaluation'''

*The information in the introduction is good but it is way too brief. The other section of the page was not introduced or not introduced properly, like the diagnosis section. Adding these bits would probably make the introduction good and a bit more informative as to what to expect from the page. Also reference them.
*The history I think is fine the way it is.
*The epidemiology is good because you have touched upon the demography of the disease and its prevalence. It would have been better if you could add a bit more statistics on the geographical distribution of the disease, as it makes the section more credible than how it already is. Unfortunately I think the section from “Screening… “ onwards is not very relevant for this section. I would consider revising as to where this information should be placed under. I guess this section needs more research overall.
*The etiology is very informative and I think you have gone in-depth in the topic, and is well researched, but I think it needs some revision. The concepts were far too technical and it makes the reader a bit too confused about what the information is actually saying. The images are amazing, and if you could incorporate them in the text it would make the section better.
*The development of the disease section I think should be the pathogenesis of the disease. This section was not done properly, as I was expecting to see how the etiology and all the clinical manifestations relate to each other; instead it was all about the clinical manifestation. I think you need to look further into this section.
*The signs and symptoms section is very informative, but I am questioning the information as it is not referenced at all in most of the paragraph.
*Diagnosis should probably changed to diagnostic tests because the diagnosis is Fragile X. The information is good for introducing the techniques to the reader. I think further description of the tests is needed.
The treatment section has some very good information on it that describes the treatments used for the disease. It could probably be better if you could highlight the actual treatments and make it stand out.
*Recent research is a bit disappointing because the most recent research that were presented is 3 years ago. As a reader, this makes me question the content of the page, whether it is up-to-date or not. It would also be good to have a more recent paper/research and the inclusion of future direction of this disease.
--[[User:Z3290841|z3290841]] 10:24, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*The lone sentence at the beginning of the history is unnecessary.

:*Essay language such as “for example” is a bit out of place on a wiki page. Tailor language to a web page.

:*In the epidemiology section some statements are not referenced. Where are these ‘examples’ coming from?

:*Research section would benefit from the bolding of paper headings or authors names.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:13, 29 September 2011 (EST)

'''Group 5 peer Review'''
* Introduction has good information, but it needs to be more catchy for readers to want to read onto the page.
* the first line of the history section seems not to be so greatly relevant to the history section. Also in the table there’s a 30 year gap at the start of the table. No important things happened during this time?
* I don’t think the information for ‘Screening/Population testing’ is necessary to be put under the epidemiology section, rather under diagnostics.
* Explanation about the genetic location of the mutation should be given. Also information found under aetiology should be re-formatted so it is easier to read.
* The development of disease section has good information. Would it be possibly to accompany these sections with images.
* Some parts under signs and symptoms are not referenced properly as it is lacking the referencing. Also possibly include some more pics/graphs/audio/movies in this section to accompany the text.
*Diagnosis section must be expanded upon. It has potential as concepts are there but more info could be included.
* Nice use of a table in the treatments section
* the paragraph starting with: ‘’ Autism is a disorder whose etiology is not…’’ should be placed to flow with the first sentence in the recent research section. It will make the paragraph flow better.
*acronym for ‘’ Autism Diagnostic Interview (ADI-R)’’ seems bit odd, what does the R stand for?
* if possible add an article from 2011 in the recent research section to make it though you are showing the reader the most cutting edge research in this field.
*Glossary must be expanded upon, many words have not yet been included.
* In the referencing section the referencing is done well. I did notice a repetition in the referencing in reference number 37 and 38. Please fix up.
* More images are needed on the page to get the image and text ration right, especially towards the middle of the page.
*other than that good page people.

--[[User:Z3291317|Z3291317]] 08:44, 29 September 2011 (EST)

Group 5

*Introduction - ok except it was a bit hard to read with the text squeezed between the two images located left and right, maybe both images could be placed on one side, such as the right, to make it easier to read and add to the continuity and flow of the page. There is a lot that could be expanded on to add to the introduction, maybe a brief explanation of the FMR1 gene and the phenotypic manifestations as a result of it being silent.
*Etiology, not really sure but i don’t think you’ve referred to the images included here, formatting could be improved with both images being on one side
*Development of the Disease – very nice heading, information easy to follow and well referenced, best heading on this page, great job.
*Signs and Symptoms – another very well organised section
*Diagnosis – this section could be best suited to a table, making each technique easy to identify and define.
*Treatment – great use of a table, information is very clear and easy to understand.
*Glossary – more terms need to be added, such as the acronyms used throughout the page: ADHD, CGG, PCR, FXS, etc.

--[[User:Z3331469|z3331469]] 07:01, 29 September 2011 (EST)

'''Group 5 Peer Review'''

• Generally good sub-heading structure. The overall flow is consistent (nice pink tables!), however I think it could be tidied up more, for example; images placed on the right hand side of the page.

• Double up’s in references need to be removed.

• Introduction is brief and concise, good!

• Epidemiology could be improved by the addition of a table, and maybe the ‘Screening/Population testing’ section could be a sub-heading on its own.

• The first paragraph in the genetic contribution of Aetiology I feel could be worded better, but nice images and really good description of the cause of the abnormality.

• Development of the disease is a really good explanatory section, really informative! The addition of images here, would really improve it (if able to find them)

• More images needed in the signs and symptoms section. Also maybe the addition of a table to sum up the different signs and symptoms with the different age groups would help. This section seems incomplete to me, where are all your references?

• Diagnosis needs some more detail and possibly an image (for completion)

• The ‘signs and symptoms’ in the Treatment section aren’t really consistent/parallel with the ‘signs and symptoms’ section itself. This could be improved by adding a similar table in the signs and section sub-heading outlining the same ‘signs and symptoms’ (just an idea)

• Glossary needs a lot more definitions.

--[[User:Z3289829|z3289829]] 02:43, 29 September 2011 (EST)

*Intro: Like the hand drawn figure but it’s not explained and most importantly, the Image is not referenced at all. Define methylation perhaps- it’s not a good idea to have introduction with a lot of terminology because you will lose your audience if they can’t understand the initial part f the page. The description of features is brief and good way to introduce the disease, it would help if you could use an image of an affected patient instead of the chromosome (which can be sued in the etiology section)/

*History: Love the colour but perhaps add a few more events, it looks very short. You can link your bolded words to a glossary.

*Epidemiology: The “screening” section doesn’t belong here. The section explained in dot points is not referenced at all. The image is great, but there is no references to the original image or any explanation of the image itself. Genetic counselling subheading also doesn’t belong in this section.

*Etiology: Clear and easy to follow but there are words that need defining in the glossary. The section would benefit if the image of the chromosome was moved here. Perhaps more explanation on the FMR gene. The first image could do with a bit more explanation. There are words in there eg: 5UTR that are not easy to understand.

*Development of disease: Good, the subheadings help and its well-formatted. Need a picture explaining the development.

*Signs and symptoms: The image is great, you can use this as your introduction to make it a bit more engaging. You should also make it bigger and explain the distinguishing features. The research is thorough!

*Diagnosis: Very short, needs more detail.

*Treatment: Love the colour, very detailed

*Glossary: Needs a lot more work! There are many words that you will need to define. For example “ allele, permutation, asymptomatic...” list goes on.

*Reference: What’s happening in references 3-8? That’s not proper referencing format. Number 41 reference – a link isn’t a reference.

*Overall: You keep referring to the disease as either fragile X syndrome or FXS. It’s best to stick to one or the other to avoid confusion. Need more interesting images. Some excellent research but it could do with a bit of work. Good job so far.

--[[User:Z3290270|z3290270]] 02:31, 29 September 2011 (EST)

'''Group 5'''

Introduction: Good pictures but they need to be bigger. Also, this section seems like a brief summary of the sections to come. I think it would be good if you included some more general background information on fragile x.

History: This section could be longer. The table would look good with some pictures in it.

Epidemiology: Great section and I like the diagram but some of the words in the diagram are hard to read.

Genetics: This section is reasonably well explained. The genetic terms need more explaining though.

Development: Good section but needs some pictures.

Signs and symptoms: Great section. Well written, flows well and easy to understand. Needs more pictures though.

Diagnosis: This section seems a bit short. Maybe you could explain how the diagnostic techniques work.

Treatment: The table seems too text heavy. Maybe add some pictures to break up the text.

Recent research: overall, good section. --[[User:Z3291324|z3291324]] 23:23, 28 September 2011 (EST)

Group 5

Hi, I can see some progress on this page which is good, content is interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: What is FMR1 gene? Need more information here, as in when was it first discovered, some stats
#* Epidemiology: I think screening information is extensive enough to be a section on its own
#* Etiology: no explanation of FMR1 gene so far, what is its normal function? Also, please refer to images used in this section
#* Development of the disease:nice succinct, easy to follow section. Perhaps add an image for one of the stages mentioned here?
#* Signs: REFERENCING!!! But, content is good and interesting
#* Diagnosis: An image here would be nice, and an explanation of how the technology is used to diagnose FXS
#* Treatment: Nice table with good information
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to balance out the text and image ratio, some good subheadings
#Content is correctly cited and referenced.
#* poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* I feel more research needs to be done here
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#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.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* Although the content is here, there is still a lot of work needed to make this page feel complete
* glossary is very lacking in terminology
* need more images
* further research would be nice to explain this disease in more detail

--[[User:Z3291643|z3291643]] 22:56, 28 September 2011 (EST)

'''Group 5:'''

•The introduction lacks referencing and is a little short, but good use of the images to gain the attention of the reader though as I was reading it I would have preferred for the images to both be on the right hand side.

•The student drawn image on the right is not explained very well and does not contain the correct copyright information.

•Is the diagnosis section finished? It seems a little short and lacking in detail, maybe add some more information to this section, perhaps also an image to help build up this heading and make it more balanced with the other sections.

•Glossary is incomplete and should be in alphabetical order

•References are repeated, but good work on the research

•Overall I liked the formatting of the page, it is easy to read visually appealing and a good use of images to balance out the text.

--[[User:Z3332183|z3332183]] 21:28, 28 September 2011 (EST)

'''Group 5'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there and well described.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Future research is well researched, but is there any other research possibilities that are on going to show breath of research? Glossary needs to be expanded - FXS as an acronym needs to be put there. Table in treatment has too much text. Put the text outside the table and use the table to summarise the content. The information in diagnosis is too brief and could go into a table. Consider expanding that section and provide more information on how and why the techniques diagnoses FXS.

'''*Content is correctly cited and referenced.'''
File:Fragile site appearance and distribution.jpg needs to be correctly referenced. Duplication of references need to be fixed. Emotional characteristics, Language and Speech, Physical phenotype and Physical phenotype section needs references.

'''*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.'''
no explanation given for File:Fragile x chromosome..jpg. more images would be good (Eg: in Fetal Development section maybe include an image of what a fetus looks like who has FXS?)

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Decent reference list and good in-text citation but is missing referencing in some areas.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Fetal development detailed.

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has followed the guidelines but some changes would be good.

--z3329495 21:17, 28 September 2011 (EST)

'''GROUP 5: Fragile X Syndrome'''
*Info in the intro is ok but could be improved by maybe including more of an explanation of the CGG codon (some may not know what a codon is and what this implicates) and a small sentence on FMR1 gene
*The placement of the two images in the introduction is a bit weird, it disrupts the end of this paragraph. Consider just putting them on the same side or putting one of them in a different section
*I don't think the first sentence of the history section is history related, looks like it could be better placed in the intro
*Timeline is ok but could possibly be researched more to include more dates, but it's good that it goes up to 2010
*I don't know if Screening/Population testing goes under epidemiology, i think it's more part of management/diagnosis
*Etiology info appears clear and concise, maybe the image of the gene would be better placed in this section
*I find the section development of disease informative and summarised well. I like the way it's structured (subheadings are fitting), an image could improve this section
*Signs and symptoms looks like its been researched extensively, info is comprehensive and summarised well, a graph or another image could improve this section and balance out the text
*Physical phenotype has no referencing (where did this info come from?)
*Diagnosis is very underdeveloped, a lot more explanation is needed for these diagnostic techniques, images could also help improve this section
*Treatment is well researched, use of a table here is suitable, however maybe you could break up the writing by splitting up the Treatment Option and Description into two different sections of the table
*Recent Research is ok, a good intro paragraph may improve this section, maybe provide more recent developments

Overall:
*Glossary is incomplete and many words need explaining, consider linking the highlighted words to the glossary as an improvement, also it might be a good idea to include acronyms in the glossary as well
*legends of images could be expanded a little more
*Reference list needs some work, I don't think links to websites are the proper way to reference

--[[User:Z3331556|z3331556]] 21:15, 28 September 2011 (EST)

'''Peer Assessment Group 5-Fragile X Syndrome'''
*The introduction contains a little bit of heavy info in it. You might want to introduce the complex concepts e.g.methylation of the CGG triplet so the reader can ease into the page.
*The absence of references in the introduction makes it feel unreliable.
*The History seems to be succinct, good work.
*Nice diagram in 'Epidemiology', however it is missing a description and copyright information
*Avoid the italics as it makes the page look inconsistent as you dont have italics very often throughout
*'Development of Disease' is divided well into distinct sub headings, easy to follow
*'Signs and Symptoms' is heavy with too much information, can you summarize some of it to condense the whole section. Also maybe consider finding some images to give it a better balance.
*'Diagnosis' requires a little more explanation of what is involved in the different types of methods.
*The table in 'Treatment' needs division of the second column maybe into treatment option and a separate description just to make it look less heavy
*'Recent Research' is structured nicely, makes it a lot easier to read
*The definitions in 'Glossary' are inadequate
*Avoid italics in the glossary
*The reference list needs some major reformatting
--[[User:Z3308968|Tahmina Lata]] 19:43, 28 September 2011 (EST)

'''Group 5: Peer Assessment'''
* Your page looks a bid 80's with all the different pinks in your table. Not a bad thing, however may be just one colour per table would be enough
* The introduction is too brief and written a little careless and lacks referencing.
* The history table is good in the way that it's chronologic and easy to read but you could write a bid more about the relevance of these events.
* Your drawing needs some copyright information and if the writing would have more contrast it would come more into account.
* The aetiology section is informative overall but some long sentences could be separated and more explanatory. Put the pictures on the same side may be to give it a bid more shape.
* The development of the disease section and signs and symptoms section read well and there is good use of subheadings.
* Is there some current research you could talk about?
* Your glossary and your references clearly need some editing and fixing up
* Overall your page seems to be written a bid careless but there are bids of interesting information in there. --z3279511 17:10, 28 September 2011 (EST)

'''Peer Assessment #5'''
*Intro looks funny with a pic on each side of the text – reconsider this formatting. Maybe both on one side and one under the other?
*Intro 1st para is very detailed for an intro- perhaps explain it more, or in more general terms. The detail will come later
*The intro sentence in history would be better in the intro.
*You keep referring to the FMR1 gene, but I have no idea what this is or how it is relevant. Please explain it somewhere! Maybe have a short para just on it and explain about it.
*In signs and symptoms, are ‘emotional characteristics’ and ‘language and speech’ meant to be their own subheadings, or subheadings of ‘intellectual development’?
*Diagnosis section is not complete, needs a lot more info and explanation of the techniques, how they work, why they are used/relevant. – Modified PCR section is too wordy.
*Treatment table is good, can you stretch it so it takes up the whole box instead of being centered? Would look better
*Recent research – surely there is more you can discuss/other areas?
*I’m sure everyone else has mentioned it, but the glossary needs work. Really, just define lots of the ‘big’ words, as you can’t assume everyone knows what they all mean.
--[[User:Z3332824|z3332824]] 11:59, 28 September 2011 (EST)

''' Group 5 Peer Assessment'''
* First student figure has no explanation as to what it's all about, and is a pretty simple diagram. What does it contain? Where is your copyright information? The same can be said with the second student-drawn figure. Make sure this is fixed!
* The introduction section appears to be pretty short. Try to keep away from using the brackets and just enter your information in a continuous format.
* The headings and subheadings work quite well. However, the lack of images in the signs and symptoms section make this difficult to read; it seems like a large block of text without anything to assist in the breakup of the page (making it difficult to read and easy for us to lose attention).
* Subheadings are used quite well. The treatment section is well presented in table format, but once again, any images to help break things up?
* The recent and future research section doesn't seem to be completed. Is there anything that can be done for the future of the disease? Is it related to any other disease processes? The glossary also seems short and isn't in alphabetic order. Please add all the terms to the glossary to ensure that there is completeness of the project! There are many terms that are difficult to understand, so slot them in here.
* There just needs to be more work done overall to ensure that the project flows smoothly and all the smaller details are accounted for. At the moment there is still a large part of the project that feels quite sketchy and requires more work.
--[[User:Z3288827|Leonard Tiong]] 10:33, 28 September 2011 (EST)

Group 5: Fragile X
*Introduction: Maybe a bit too concise, some of the content that should be in the intro is missing. Maybe this should be redone with references! Also, it doesn’t draw the reader’s attention unfortunately.
*History: Simple table, but a small explanation regarding the significance of the discoveries would be very helpful.
*Epidemiology: Nice picture, had to tilt my head a little. The “Screening/Population testing” seems like a whole new section itself. Might have to look into that?
*Etiology: This section was very well managed.
*Development: I like the subheadings, maybe an image to help add some visuals, but not required.
*Signs and Symptoms: This again, was well done, though detailed, the mass text was slightly disorientating, another image perhaps?
*Diagnosis: Looks incomplete, more info required, probably another sub-heading would do.
*Treatment: Best section in this webpage. Detailed and neatly laid out.
*Glossary: Some explanations and a few more words added here would do the trick!
*Overall: The basic fundamentals are there, some more info here, and a few tweaks there is all that is needed! Keep it up.
--[[User:Z3332327|Lisa Xiao]] 01:25, 28 September 2011 (EST)

'''Group 5'''

*Introduction should be explained a little better and also referenced
*Hand drawn image needs the correct referencing/copyright info
*Good use of subheadings in epidemiology
*Etiology is a little hard to follow
*Development of disease needs an image to break up the text
*Signs and symptoms is very text heavy- try to change it up a bit i.e. use of dot points
*Good use of table in treatment
*Glossary needs to be extended
*Overall, this has potential to be a good project with a few adjustments

'''Group 5'''

*Introduction: too much detail, give an overview. Only one of the images would be enough.

*History: well done

*Epidemiology: screening / population testing should be a separate section, very good image

*Etiology: well done,

*Development and Symptoms: both sections are clear and easy to follow, good use of subheadings

*Diagnosis: seems incomplete

*Treatment: very detailed

*Research: I would add some other examples. If you want to outline only autism, maybe change the heading.

*Glossary: there is a lot missing

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 21:31, 27 September 2011 (EST)

'''Group Peer assessment'''
*Introduction images placement may work better on one side or below the information though current placement is confusing affecting text as well.
*History requires more elaboration as well at least indication of the founder in the introduction of the history even an image of the founder would benefit this section, although the timeline is nicely done.
*Development and disease would be better as a sub heading under eitology as development of the disease links with the causation of the disease.
*Glossary needs work done as most terms are genetic related and those without a genetic background will find difficulty understanding the web page.
*Referencing only needs to adjust the links, links need to be sited properly manually.
z3332250 23:50, 26 September 2011 (EST)

Group 5 Peer Review

*Introduction does not entice the reader to read the rest of the page. Maybe less scientific language in the introduction?
*Table under history is well presented and visually appealing
*“Postnatally” and “postpubescent” need to have “development” added to the subheadings
*Well referenced
*The consistent colour scheme throughout is a nice touch
*Another image under signs and symptoms would make this section look more balanced
*Diagnosis seems brief-add information or perhaps merge with another subheading
*Glossary needs to be expanded
*Logical, clear and organised structure
*Overall, a good page. The bulk of it is there. If each section just changed some minor things, this page would improve greatly.
--[[User:Z3308965|Fleur McGregor]] 19:38, 26 September 2011 (EST)

'''Strengths:'''
*The use of same reference for different part of the page is good.
*The treatment section is put together.
*Images are appropriate and useful.
'''Weaknesses:'''
*Formatting is not as best as it could be.
*For some sections, punctuation is a slight problem.
*The flow under the epidemiology section doesn’t seem quite right. Seems to give a disjointed feel.
*The section under Diagnosis could be further elaborated.
'''Specific corrections:'''
*Maybe testing and counselling can go under a new heading, “Management”.
*The subheadings “Post Natally” & “Postpubescent” could be changed to “Post Natal Development” & “Post Pubescent Development” instead to give it a uniform formatting.
*Some of the words in the page should be in the glossary section e.g. tactile defensiveness and face encoding.
*Improve format for some of the references.
*Include explanations and the copyright statements on student images allowing for re-use for wikiusers.

--Z3389806 07:34, 26 September 2011 (EST)

'''Group 5 Critique'''

#• Introduction should not contain clinical manifestations. It should introduce the topic as a whole. This section needs to be re-written
#• The history section is ok. The timeline could be explained a little better to give a clearer view of what the history of the disease is to the reader
#• Epidemiology should not contain the advantages and disadvantages of population testing. This should be another section in itself
#• Aetiology was fine
#• Development of the disease was ok
#• Signs and Symptoms was good
#• Diagnosis needs to be more detailed than what it is
#• Treatment and recent research is impressive
#• Glossary needs more terms added to it. It is too short, however that will be fixed when you add more explanations to the other sections and define the terms here.

--[[User:Z3289991|Robert Klein]] 18:57, 24 September 2011 (EST)

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

* I liked your page as it had a simple and easy-to-follow lay out
* Some of the images could have been made larger on your actual page just so that it adds dynamics to your page
* I was left wanting to know more about the diagnosis, this section was quite brief
* I personally found your treatment table hard to read because there was so much information. Personally I believe that maybe dot-point form could have been used to get your main points across.
* Perhaps expand upon your glossary as there were some words that weren’t in there that maybe should have been.
--[[User:Z3332629|z3332629]] 15:25, 22 September 2011 (EST)

'''Group 5 Assessment'''
*The Fragile X Chromosme. Jpg needs both an explanation and referencing.
*There is no referencing in the Introduction section. Where did you get this information from?
*History- Good idea to setup using a chart to organize the data. First time I’ve seen that.
*Fragile X Inheritance jpg looks great!!! Way to incorporate the data into a figure. However, it does still need citing.
*Not all the information in the Screening/Test Population is cited. Where is this information referenced from?
*The Development of Disease portion could use a figure or two to make it more appeasing to look at.
*Some of the information under Signs and Symptoms is also not cited. Where was this information drawn from?
*Good chart under the treatment section. However, maybe try a bullet list on the right hand column to help set the ideas apart from each other?
*The glossary link seems a little short… Are you sure there aren’t any more words which would be helpful to define for the audience?
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
*Overall, good work! Just work on the referencing and some of the visual aspects.
--[[User:Z3391078|Z3391078]] 15:09, 27 September 2011 (EST)

Group 5
* Straight into it hey- a little bit more of an “introduction” might help sorry. The first line kind of scared me. Yes it is relevant information but I think you need to almost ‘warm the reader up’ if you know what I mean. When reading anything I don’t think jumping straight into the nuts and bolts of how it works benefits anyone. I think you should start with what it is and why it is important that the reader learns about your topic
* The history section is brief and I don’t actually understand the relevance of the discoveries. While putting the information in a table shows that you know how to format it to look pretty, it is not the most effective way of showing
* Your hand drawn images still need to be referenced and copyright put on them
* Reading through I am overwhelmed by the content. This may be due to a lack of proper introduction or early explanation. I feel like the information isn’t as accessible as it could be
* Development of the disease would work well in a table I think
* Maybe put the clinical manifestations into dot points? I just feel like everything is a bulk of text and it would be better if you broke it up a little
* An image in diagnosis would help
* Treatment works well in a table
* Glossary could be extended
* You are on the right tract it is just a very heavy project. The content is all there but I found it really hard to get through.

'''Group 5'''
* Great structure with headings and subheadings, very easy to follow and read.
* Nice succinct intro. good over view of the disease. - Maybe you could dot point phenotypic abnormalities
* Some areas a little text heavy, additional pictures would fix this problem. for example some more pictures in signs and symptoms.
* Good simple history, well researched. easy to follow.
* Maybe Screening/Population testing could be its own heading.
* Great section on development of disease! I like the format very interesting relevant information! well done!
* Treatment section well put together but a little text heavy- try condensing info or bullet points.
* Make sure all the pictures are referenced properly.
* Nice to see your references grouped.
* NIce student drawn picture.
* Make sure all your acronyms/ scientific lingo is in the glossary.
* I liked that you has a continuous colour scheme for your tables. It makes your page look very neat.
* The bottom of the page is a little text heavy.

*'''Introduction''': Concise and to the point.
*'''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.
*'''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.
*'''Screening/Population testing''': Looks fine.
*'''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.
*'''Development''': Well explained, good use of subheadings.
*'''Signs and Symptoms''': Also well explained, good use of subheadings.
*'''Diagnosis''': Too short. What about non-genetic diagnosis?
*'''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?
*'''Recent Research''': The autism related bit is well explained, but is there no current research looking at other aspects of the disease?
*'''Glossary''': Too short, more terms need to be explained.
*'''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.
*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?

'''Group Project 5'''

*The introduction was too in detail and did not seem like an introduction. Also there are no references ?
*the history is easy to read
*Etiology - very nice section of information
*Development of the Disease - was a good idea to put this in and the information is easy to read, maybe include some hyperlinks to the glossary?
*The treatment table is quite informative and easy to read due to its structure and quite appealing to the eyes
*More should be added to the glossary

--[[User:Z3330313|z3330313]] 20:02, 28 September 2011 (EST)

'''Peer Assessment: Group Project 5'''
*The introduction has no references.
*More pictures in the sections on development, signs and symptoms and diagnosis would help to make the written work easier to follow. Examples of pictures that could be added are images of neural crest development put in the development section or images of diagnostic techniques in the section on diagnosis.
*The section on treatment is clear and informative.
*The different diagnostic procedures could be explained more, such as how they are each conducted.
*Instead of having the uncommon words highlighted in bold, maybe you could link the words to their definition down in the glossary section.
*Some of the references are duplicated. They can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
*In conclusion, this project is both accessible to people who have no great scientific knowledge, but also delves into quite specific knowledge. A good balance.
--[[User:Z3217345|z3217345]] 21:59, 27 September 2011 (EST)

'''Peer Review'''

* the layout was not well structured
* was able to understand the disorder

--[[User:Z3060621|z3060621]] 21:31, 28 September 2011 (EST)

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{{2011GroupDiscussionMH}}

=='''Discussion'''==

'''BORIS!'''
This is what you missed in todays lab: you need to read through the peer review comments and work on the comments that are applicable to your section (although you don't have to agree with all the comments), it is also now time to work on all the sections together and we still need more pictures (make sure they are referenced properly and include the student template - if we have any material not cited properly, Mark is going to delete it), we also need to look into maybe adding videos to our page and Sandra would like us all to contribute to the recent research section. We have 2 weeks to finalise our wiki and our page will be closed at 11am two Thursdays from now. Thanks!

--[[User:Z3290815|Tara Lofthouse]] 19:13, 29 September 2011 (EST)

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Collins SC, Coffee B, Benke PJ, Berry-Kravis E, Gilbert F, et al. (2010) Array-Based FMR1 Sequencing and Deletion Analysis in Patients with a Fragile X Syndrome–Like Phenotype. PLoS ONE 5(3): e9476. doi:10.1371/journal.pone.0009476

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Nice work Sandra! I will keep looking and i see you changed your table to pink too haha --[[User:Z3290815|Tara Lofthouse]] 20:54, 18 September 2011 (EST)

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Hey guys, i have just edited our group page and put up 3 pictures! Please try to find more before Monday (especially under development of the disease and signs and symptoms as these parts are so dense with writing and thus need pictures to break it up a little bit)! Cheers, --[[User:Z3290808|Sandra Issa]] 00:24, 18 September 2011 (EST)

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Here:

http://3.bp.blogspot.com/-88xXtruHpyo/TlaALBe6CaI/AAAAAAAABx8/ZMdZULFKEns/s1600/happy%2Bcamper.jpg

{|
|-
| Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)
| 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. Stimulants have been shown to improve ADHD symptoms in FXS patients. These drugs are distributed in addition to individualized therapies and behavioural intervention.
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.
Clonidine has shown to be helpful for children with ADHD who have sleep disturbances (a asymptom often present in FXS patients). Guanfacine can also improve ADHD symptoms, such as “including hyperactivity and frustration intolerance, as well as hyperarousal.”
|-
| Treatment of Mood Instability and Aggression
| 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.
Risperidone was the most popular and clinically effective antipsychotic drug in the past for treatment of aggression and mood instability in patients of FXS. “The typical risperidone dose range for children with FXS is 1 to 2.5 mg/day.”
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.”

|}

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Hey guys, yep i will be there at 10 count me in! --[[User:Z3290808|z3290808]] 09:42, 15 September 2011 (EST)

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It looks like it is going to be late nights all round. We should try and pump out an intro in that time tomorrow as well as at least one image? --[[User:Z3290815|Tara Lofthouse]] 18:52, 14 September 2011 (EST)

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Okay, Tomorrow at 10am it is. I'll finish my stuff off tonight (it looks like being a late night :P).
I'm assuming that it doesn't have to be perfect by tomorrow. It just needs to look alright, so that people can give us feedback before we finish it, yeah?
Also, Boris, Interview is on the 27th. I was just visiting a friend. I'll tell you how it goes though, when it does happen. --[[User:Z3290618|Ziggy Harrison-Tikisci]] 17:43, 14 September 2011 (EST)
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I can make it at 10am on Thursday as well --[[User:Z3290815|Tara Lofthouse]] 12:08, 14 September 2011 (EST)

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Ooo, interview? How'd it go?
I don't have time to meet up today (Wednesday), but I can see you guys in the lab at 10 tomorrow, before the class.
--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)--[[User:Z3290689|Boris Zolotarev]] 10:39, 14 September 2011 (EST)

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Hey Guys, Sorry I've been in Melbourne for the week, so haven't done any work. Getting on it now. Going to do all my referencing, editing etc.
Wanted to ask if there is a time when we can get together, go through it all and make it pretty. Did we just want to do this before our lab on thursday, or if you guys have some time on wednesday afternoon?
Furthermore, how harsh is the criticism/feedback? Doesn't mince his words, does he? --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:51, 12 September 2011 (EST)

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Hey Boris yes i am experiencing the same problem. I cannot see the references and the reference list looks like a bunch of arrows facing superiorly. I got a bit worried but then checked the other groups and they had the same issue. I'm not sure what we can do? Let me know. ---[[User:Z3290808|Sandra Issa]] 09:49, 9 September 2011 (EST)

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WHAT HAPPENED TO OUR REFERENCES. Can you guys do me a favour and tell me if you can see them? I was trying to put in an image just then and when I did the save it came up with references wiped. I tried undoing my last edit to no avail. There are still 30 something references, there's just nothing IN them. When I finished my word edit earlier today I actually saved the ENTIRE script as a word document; when I tried to rewrite EVERYTHING with that same (working) script it still came up with stuffed up references.

Let me know if you guys see the same problem. If you do, I'll have to get in contact with Mark Hill to fix the script.
--[[User:Z3290689|Boris Zolotarev]] 23:31, 8 September 2011 (EST)

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I hate how the times shown on the editing thing are totally out of whack....can I post anything up at the moment? ><
--[[User:Z3290689|Boris Zolotarev]] 23:27, 7 September 2011 (EST)

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Hey guys, i have just added the diagnosis part of our page and have also finished the treatment. Let me know if you think the treatment is too long? Or if you want to make any changes to the "Recent Research" part of our page.

Also, i will add in more references for this part very soon. I have put in a general reference (review article) but will make sure i include all references used very soon.

Have a good night, --[[User:Z3290808|Sandra Issa]] 21:16, 7 September 2011 (EST)

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Suggestion: rename '''Development of disease''' to '''Progression of disease'''. Also, I should have a heap up later tonight, I'm compiling it all in a separate document at the moment.

--[[User:Z3290689|Boris Zolotarev]] 15:39, 7 September 2011 (EST)

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Hey guys, just letting you know that i have found a great article which addresses many current 'treatments' for FXS. Also, i have found another article which summarises the current methods of diagnosing FXS. I will add this information (what i think is most relevant from the articles) onto our group page under the headings "treatment" and "diagnosis" '''very soon'''. Please feel free to add in anything that you believe i have not addressed under these headings. Also, i will try to edit our page as a whole soon so that it looks more uniform in appearance. Over the next couple of days we should all read each of the sections and try to add in additional information that someone else may have missed. Also, a reminder to keep an eye out for relevant pictures that have unrestricted access to add onto our page!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:32, 5 September 2011 (EST)

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Hey, I'm doing a whole bunch now. I'll properly reference it all later, but I'm getting a lot of it off the american National Institute of Health. They've got references for all of it. So when I have more time, I'll go through those references, add them, and edit the information. So, what I put on the group page will just be an overview. Also, you people should go to bed earlier :)
http://www.nichd.nih.gov/publications/pubs/fragileX/sub6.cfm
--[[User:Z3290618|z3290618]] 09:49, 1 September 2011 (EST)

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z3290808: I don't know why it wouldn't let you save, i wasn't editing at that time. Try again and if it doesn't work maybe paste your work here with your references and one of us can put it onto the project page for you?

Boris: At least something is up :) My section needs a lot more editing and a lot more cross checking with other references as well.. Any progress is good progress at the moment
--[[User:Z3290815|Tara Lofthouse]] 03:35, 1 September 2011 (EST)

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Heya, I took a stab at my section but I'm a bit dead at the moment '''(points to timestamp)'''. I'll try get some more done tomorrow between the lecture and lab.

On the plus side, I added another 6 or 7 references to our thingy ^^

--[[User:Z3290689|Boris Zolotarev]] 01:28, 1 September 2011 (EST)

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Guys it's not letting me save what i have written onto the group page! Is anyone currently on and trying to edit at this same time?
--[[User:Z3290808|z3290808]] 22:41, 31 August 2011 (EST)

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Yo Boris, You do Etiology, I'll do signs and symptoms. We can work towards the middle.
That leaves history and epidemiology to Tara and Recent research to Sandra. And then we can all refine it/make an intro.
We can at least do that to start with.
Also: can everyone contribute to the glossary. If you find any terms that people (eg. me) wont understand, please keep them.--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:10, 25 August 2011 (EST)

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The only reason why we need to put our names down now is to satisfy the weekly individual assessment but of course we can change things. Just put your name down for epidemiology or whatever was left over and we'll discuss it tomorrow. Maybe if we could get to the lab 10-15min earlier because we never get enough time at the end of the lab?

--[[User:Z3290815|Tara Lofthouse]] 19:50, 24 August 2011 (EST)

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Just skimmed through this (damn I left it late >< ), should I nominate something now or should we discuss it tomorrow?
Also, what do you guys think of having some sort of realtime chat method? Facebook or something of the sort...
--[[User:Z3290689|Boris Zolotarev]] 19:17, 24 August 2011 (EST)

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Yeah i know but the ones i put my name down for are really not that lengthy. We definitely need to have a chat tomorrow.
--[[User:Z3290815|Tara Lofthouse]] 17:45, 24 August 2011 (EST)

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Hey guys, you haven't left much for Boris and i to do lol .. I don't mind doing the recent research part - focussing on autism and fragile x.. but then i don't know what Boris would do? I will sign my name for now but i think we will have to change it around a little to better make the work load equally spread.

Cheers, --[[User:Z3290808|Sandra Issa]] 16:17, 24 August 2011 (EST)

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I've taken it all on board and changed it. I'm fine for you to do whatever you want but doing both the genetic component and the signs and symptoms might be a lot of work. As long as everything is spread evenly i don't mind :)

--[[User:Z3290815|Tara Lofthouse]] 16:35, 23 August 2011 (EST)

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Hey, I was wondering if anyone minds if I do 'Genetic contribution'. Also, is it okay if I follow the timeline of the disease? I will start with the chromosome, saying what the defect causes at a molecular level, and then when it first presents, and how it affects the development etc up until how it presents in the adult. Which means I'd probably do "Signs and symptoms (clinical Presentation)" as well.
ALSO, we need to do a brief history of the disorder. So, below I've just tweaked the layout Tara and Sandra put up: let me know what you think

* Introduction
* History of Disease
* Epidemiology
* Etiology
** Genetic contribution
* Development of Disease
** Fetal Development
** At birth
** In Adult
*** Signs and symptoms
* Recent research
** Fragile X and Autism
** Diagnosis
** Treatment
--[[User:Z3290618|z3290618]] 15:18, 23 August 2011 (EST)

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Yeah, i think it makes sense how you've got it Sandra. However like Boris said maybe instead of having the heading "Autism and Fragile X Syndrome" maybe we could have recent research/current studies or something along those lines and include it there along with diagnosis and treatment? Do you think that etiology is too similar to genetic contribution?

ALSO!!!
What headings would you like to research? I set up a "Who's doing what?" heading on this page to sign your name next to.

--[[User:Z3290815|Tara Lofthouse]] 12:39, 23 August 2011 (EST)

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Hey guys, i have come up with a couple of headings that we can use:

* Introduction (short summary)
* Epidemiology
* Signs and Symptoms (Clinical Presentation)
* Etiology
* Genetic Contribution
* Autism and Fragile X syndrome
* Diagnosis?
* Treatment?
* References

Tara i also like the format that you have included below.. i basically have made something similar but in different order based on what i think should come first perhaps? The ones with a question mark beside them are ones that i am unsure if we should include or not. Let me know what you think!
Cheers,
--[[User:Z3290808|Sandra Issa]] 12:03, 23 August 2011 (EST)

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Hahaha of course it's your place to say so.. good suggestion, i'll fix it up now and if we want to change it again than that's no problem. I just thought i'd put something up to get started and we can go from there. What i've done is no where near completed.
--[[User:Z3290815|Tara Lofthouse]] 18:52, 22 August 2011 (EST)

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(I know it's not my place to say so before I've submitted my own suggestion but) I think I'd put "Autism and Fragile X Syndrome" within the "recent research" subtopic. I'll put up a suggestion by tomorrow evening, if not earlier.
--[[User:Z3290689|Boris Zolotarev]] 09:27, 22 August 2011 (EST)

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'''Hello everyone,''' what do you think about using the following headings for our project? Are there ones that you think we could omit or ones that you would like to add? We also need to decide on who is doing what.
* Signs and symptoms
* Diagnosis
* Genetics
* Etiology
* Epidemiology
* Treatment
* Recent research
** Autism and Fragile X Syndrome
* References

--[[User:Z3290815|Tara Lofthouse]] 16:26, 21 August 2011 (EST)

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[http://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Lab_2_-_Group_Project Group project] --[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:58, 4 August 2011 (EST)

[http://www.ncbi.nlm.nih.gov/omim OMIM]--[[User:Z3290618|Ziggy Harrison-Tikisci]] 12:59, 4 August 2011 (EST)

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Here's another interesting topic.

[http://en.wikipedia.org/wiki/Apert_syndrome Apert Syndrome aka acrocephalosyndactyly] --[[User:Z3290689|z3290689]] 11:38, 11 August 2011 (EST)

=='''Congenital Hypomyelinating Neuropathy'''==

What do you guys think you of this topic [http://omim.org/entry/605253 Congenital Hypomyelinating Neuropathy]?

There are quite a few articles on it:

Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination.

Analysis of congenital hypomyelinating Egr2 Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination.

P0 Glycoprotein Overexpression Causes Congenital Hypomyelination of Peripheral Nerves.

Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg–Hirschsprung disease: Phenotypes linked by SOX10 mutation.

A lot of them overlap with their findings and the focus of their studies, so it seems to be a pretty thorough topic.

--[[User:Z3290689|Boris Zolotarev]] 21:03, 7 August 2011 (EST)

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I’m all for doing '''Congenital Hypomyelinating Neuropathy''' as our topic.

Here are some articles I have found:

'''Research Articles:'''

[http://neuro.cjb.net/content/29/8/2312.full.pdf+html Congenital Hypomyelinating Neuropathy with Lethal Conduction Failure in Mice Carrying the Egr2 I268N Mutation]

* 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

[http://jnnp.bmj.com/content/48/12/1269.full.pdf Congenital hypomyelinating neuropathy]

* 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:'''

[http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TBD-3W37BMX-C-1&_cdi=5140&_user=1975841&_pii=S0887899498001386&_origin=&_coverDate=03%2F31%2F1999&_sk=999799996&view=c&wchp=dGLzVzb-zSkWA&md5=d2e9e64dfc821d71ec81675f01932b8a&ie=/sdarticle.pdf Congenital hypomyelinating neuropathy: two patients with long-term follow-up]

* 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

--[[User:Z3290815|Tara Lofthouse]] 12:22, 9 August 2011 (EST)

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=='''Fragile X Syndrome'''==

==='''Articles'''===

Hey guys,
I had a look at Congenital Hypomyelinating Neuropathy and to be honest i did not find it very appealing. I found the disorder "Fragile X Syndrome" to be very interesting! Can you guys please check out the following link on [http://www.fragilex.org/html/cause.htm/ Fragile X Syndrome] and let me know if the disease also interests you!? I found the information on it is quite extensive and the disease is well known. If you do not want to base our project on this syndrome, i am sure we can decide on one we can all enjoy studying! :)

Here are some interesting articles that i have found on '''Fragile X Syndrome''':

* '''Review Article''': Fragile X syndrome: from gene discovery to therapy <ref><pubmed>21196228</pubmed></ref>

- This review focuses on the molecular and biochemical pathways shown to be relevant in the Fragile X Syndrome. It describes that a mutation in the FMR-1 gene was found to lead to Fragile X Syndrome due to excessive repeats of the trinucleotide sequence CGG which is known to inactivate the FMR-1 gene, making the X chromosome fragile and prone to breakage. This review article also demonstrates the many vital functions of the FMR-1 gene such as its role in RNA transport and stability, thus absence of the protein transcribed and translated from this gene is thought to affect brain development and thus leads to signs of mental retardation.

* '''Research Article:''' DNA methylation represses FMR-1 transcription in fragile X syndrome <ref><pubmed>1301913</pubmed></ref>

- This research article explores the two molecular differences of the FMR-1 gene in normal individuals vs. those with Fragile X Syndrome. These differences are an increase in size of an FMR-1 exon containing a CGG repeat and abnormal methylation of a CpG island 250 bp proximal to this repeat. This research article also shows how these two abnormalities repress transcription of the FMR-1 gene, leading to the absence of the FMR-1 protein which is thought to be the contributing factor to the Fragile X phenotype.

--[[User:Z3290808|Sandra Issa]] 19:53, 9 August 2011 (EST)

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Here are some articles I have found for '''Fragile X syndrome''':

'''Research Article:''' The state of synapses in Fragile X Syndrome <ref><pubmed>19325170</pubmed></ref>

* Fragile X Syndrome is the most common inherited form of mental retardation and a leading genetic cause of autism.

* Evidence that suggests alterations in synapse number, structure and function are associated and contribute to both Fragile X Sydrome and autism.

* Fraile X Syndrome is caused by loss of function of the Fmr1 gene which encodes the RNA binding protein, FMRP (FMRP is present at synapses where it associates with mRNA and polyribosomes).

* FMRP is also has a role in synapse development, elimination and plasticity.

* An understanding of the molecular and synaptic function of FMRP, as well as the consequences of its loss, has led to the early developments of therapeutic strategies for Fragile X Syndrome.

'''Research Article:''' Fragile x syndrome: history, diagnosis, and treatment. <ref><pubmed>6348096</pubmed></ref>

'''Review Article:''' Systematic review of pharmacological treatments in fragile X syndrome <ref><pubmed>19822023</pubmed></ref>

'''Review Article:''' FMR1 and the fragile X syndrome: human genome epidemiology review <ref><pubmed>11545690</pubmed></ref>

--[[User:Z3290815|Tara Lofthouse]] 14:37, 16 August 2011 (EST)

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==='''Images'''===

[[File:FMR4 is silenced in fragile X syndrome.jpg|thumb|FMR4 is silenced in fragile X syndrome]]

[[File:FMR4 is silenced in fragile X syndrome.jpg|350px]]

File:FMR4 is silenced in fragile X syndrome

--[[User:Z3290808|Sandra Issa]] 10:20, 14 August 2011 (EST)

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[[File:Hippocampal_Formation.jpg‎|thumb|Hippocampal_Formation]]

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

File: Hippocampal_Formation

--[[User:Z3290815|Tara Lofthouse]] 13:49, 17 August 2011 (EST)

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Like?
[[File:Fragile site appearance and distribution.png|300px]]
File: Fragile site appearance and distribution
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 08:55, 18 August 2011 (EST)

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[[File:Journal.pone.0013559.g001.png‎|thumb|FXR1 (A) and FXR2 (B) crystal structures]]

[[File:Journal.pone.0013559.g001.png‎|300px]]

File: FXR1 and FXR2 crystal structures

--[[User:Z3290689|Boris Zolotarev]] 11:00, 18 August 2011 (EST)

== '''Who's doing what?''' ==

* Introduction = DO AT THE END!!!!
* History of Disease = Tara
* Epidemiology = Tara
* Etiology = Boris
** Genetic contribution<ref>http://www.fragilex.org/html/premutation.htm</ref><ref><pubmed>10208170</pubmed></ref><ref><pubmed>11445641</pubmed></ref><ref><pubmed>12638084</pubmed></ref><ref>http://ghr.nlm.nih.gov/condition/fragile-x-syndrome</ref><ref><pubmed>8348153</pubmed></ref>
** Development of Disease
*** Fetal Development
*** At birth
*** In Adult
* Signs and symptoms = Ziggy
** Physical phenotype
** Social interaction
**Intellectual development
* Recent research = Sandra
** Fragile X and Autism
** Diagnosis
** Treatment
* References

==ZIGGY'S STUFF==
Just leaving this here for the next hour, so that I don't have to retype it all (can't get wifi in the embryo lab).

The hallmark of the fragile X syndrome is mental retardation, which was noted as early as 1943 in a report of a large family with 11 mentally retarded males and two mildly retarded females. 64 The clinical phenotype associated with the syndrome has since been widened to include a variety of cognitive, physical, and behavioral characteristics (reviewed in Mazzocco). 65 Almost all males with the full mutation exhibit some clinical features of the fragile X syndrome. Also, most affected males do not reproduce, presumably due to the severity of mental retardation. With regard to cognitive function, affected males often exhibit developmental delay very early in childhood. By the age of 3 years, most males will test in the mentally retarded range. 66 Ultimately, almost all males with the fragile X syndrome are mentally retarded, with severity ranging from profound (IQ <20) to mild mental retardation (IQ 50–70), with most being moderately retarded (IQ 40–54) (reviewed in Hagerman). 67 Physically, adult males often have a long narrow face, prominent ears, a prominent jaw, and macroorchidism (reviewed in Hagerman). 67 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, and mitral valve prolapse (reviewed in Warren and Sherman). 8 Males with the fragile X syndrome also tend to exhibit behavioral features such as hyperactivity, social anxiety, perseverative speech and language, tactile defensiveness, stereotypies (e.g., hand-flapping), and hand biting (reviewed in Hagerman). 67 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. 68 The association of fragile X with autism, however, is not clear because the proportion of males with the fragile X syndrome meeting the diagnostic criteria for autism seems to diminish with age. 68

Physical phenotype
Before puberty, children with Fragile-X tend to have no discernable 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. 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 macro-orchidism: enlargement of the testicles. Fragile-X patients may also have loose connective-tissues, allowing their joints to be more flexible that normal. This may cause complications arising from increased risk of 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.

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. Their anxiety often manifests itself as discontinuous speech and a lack of eye contact.

Results indicate that compared to the control group, individuals with FXS exhibited decreased activation of prefrontal regions associated with complex social cognition, including the medial and superior frontal cortex, during successful face encoding. Further, the FXS and control groups showed significantly different relationships between measures of social anxiety (including gaze-fixation) and brain activity during face encoding. These data indicate that social anxiety in FXS may be related to the inability to successfully recruit higher level social cognition regions during the initial phases of memory formation.
Reference: Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome.

Intellectual development
As a generalisation, the majority of Fragile-X patients have an IQ between 1 and 2 standard deviations below the population mean. This equates to around 40-85. Few Patients lie out-side this range, with approximately 20% within the ‘normal’ range (85-115) and less below 40. Females however, show lower impairment, with only one-third having IQs within the ‘mental retardation’ range.
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.
Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points.

Studies of intellectual function in FXS often demonstrate a mean IQ decline of 4 to 9 standardized points over intervals ranging from several months to 13 years.
Reference: Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Working Memory
First, when individuals affected by the premutation are examined as a group, they exhibit a weakness only for tasks that reflect functioning of the central executive subcomponent of working memory.

Second, when both permutation sub-groups are examined together, the extent of the central executive deficit is significantly correlated with larger CGG repeat expansions.

For permutation males who are asymptomatic, mild executive dysregulation, inhibitory deficits that worsen with age, and declarative verbal learning and memory are notable.

The detection of a deficit in the central executive component of working memory in the fourth decade of life that progressively deteriorates with age suggests a cumulative process that may be a cognitive correlate to the underlying degenerative process identified in premutation males.

The significant correlation between CGG repeat length and central executive working memory in asymptomatic carrier males suggests greater neuropathology in carrier males with larger expansions in FMR1 mRNA transcripts.
Reference: Lifespan changes in working memory in fragile X premutation males

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.

== '''References''' ==
<references/>

2011 Group Project 5

2011-10-12T03:52:26Z

Z3290618: /* Physical phenotype */

{{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 premutatuin carrier;
** FXTAS: Fragile X-associated tremor/ataxia syndrome is a late onset 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 counselling and education
* There is a concern for the availability of resources

== Diagnosis ==

Modern-day approaches to diagnosing FXS involve the use of 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.

'''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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{{2011Projects}}

2011 Group Project 5

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= 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="PMID2018070"><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="PMID2018070"/>. 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 premutatuin carrier;
** FXTAS: Fragile X-associated tremor/ataxia syndrome is a late onset 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 counselling and education
* There is a concern for the availability of resources

== Diagnosis ==

Modern-day approaches to diagnosing FXS involve the use of 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.

'''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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= 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. 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 premutatuin carrier;
** FXTAS: Fragile X-associated tremor/ataxia syndrome is a late onset 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 counselling and education
* There is a concern for the availability of resources

== Diagnosis ==

Modern-day approaches to diagnosing FXS involve the use of 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.

'''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/>

----

{{2011Projects}}

2011 Group Project 5

2011-10-12T03:44:47Z

Z3290618: /* Physical phenotype */

{{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. Mitral valve prolapse has been shown to in late adolescence . 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 premutatuin carrier;
** FXTAS: Fragile X-associated tremor/ataxia syndrome is a late onset 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 counselling and education
* There is a concern for the availability of resources

== Diagnosis ==

Modern-day approaches to diagnosing FXS involve the use of 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.

'''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/>

----

{{2011Projects}}

2011 Group Project 5

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= 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, and mitral valve prolapse. 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 premutatuin carrier;
** FXTAS: Fragile X-associated tremor/ataxia syndrome is a late onset 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 counselling and education
* There is a concern for the availability of resources

== Diagnosis ==

Modern-day approaches to diagnosing FXS involve the use of 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.

'''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/>

----

{{2011Projects}}

2011 Group Project 5

2011-10-12T03:35:56Z

Z3290618: /* Signs and Symptoms */

{{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, 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, and mitral valve prolapse. 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 premutatuin carrier;
** FXTAS: Fragile X-associated tremor/ataxia syndrome is a late onset 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 counselling and education
* There is a concern for the availability of resources

== Diagnosis ==

Modern-day approaches to diagnosing FXS involve the use of 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.

'''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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{{2011Projects}}

User:Z3290618

2011-10-06T00:22:19Z

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2011-09-29T01:56:22Z

Z3290618: /* Attendance */

User:Z3290618

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Talk:2011 Group Project 6

2011-09-29T00:43:49Z

Z3290618:

[[2011_Group_Project_6|'''Group 6''']]: [[User:z3290841]] | [[User:z3291317]] | [[User:z3291324]] | [[User:z3291423]]

{{2011GroupDiscussionMH}}

==Peer Review==

'''Peer Review'''
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

Group 6:

Great intro, brief but covers everything. Good amount of references for the information provided
Genetics part was covered well.

The reference under diagnostic techniques should be with the other references and hopefully, by the end of semester there will be images where it says “insert images”

Good use of tables.

Maybe a few more pictures and the page will be perfect.

Evidently there’s been good work put in and the information has been researched well.

9-13 are all the one link so it should be one link not 5 separate links.

Clear and concise

z3332178 =]

'''Peer Review'''

*Introduction: the layout is a bit messy. Maybe get rid of the double spacing. It might also be a good idea to include an image e.g. maybe of a heart. Needs to include more references in this section.
*History section was well written. I suggest putting the quote in a blue box or highlighting it in some way to make it stand out. Try including a table or timeline to summarise the key events and findings.
*Signs and symptoms; Good layout and presentation of information. Easy to follow and understand.
*Genetics: shows it has been thoroughly researched. Like the use of images to compliment the text. Try and put the information in a table. The section is too lengthy in comparison with the other sections. Needs to hyperlink certain technical words to the glossary.
*Pathophysiology: well written. The information is concise and easy to understand. Good use of student drawn images.
*Great idea summarizing the information on 'diagnostic tests' in a table. Get rid of the in text referencing in the table.
*Add a border around the table in the treatment/management section.
*Other sections; good information. The referencing need to be fixed, it's not consistent. Try and include more images or tables in the prognosis, future directions sections to break up the heavy text. These sections seem a bit mundane compared with the rest. Prognosis section required more referencing.
*Glossary; need to be expanded.
--[[User:Z3291622|Z3291622]] 10:06, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*Introduction does not flow very well. Sentences are very choppy.

:*History section would benefit from a timeline rather than paragraphs as it is a bit hard to follow.

:*In the epidemiology and symptoms sections need some more content. Seems very minimal. Also images?

:*Diagnostic section needs the rest of the information added to its table. “Insert text here”. Also use of bolding or different font sizes would benefit this table.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:19, 29 September 2011 (EST)

Group 6 Peer Review

*Majority of page is in a logical and organised manner however maybe switch aetiology and signs and symptoms to make it flow better?
*History section had good, clear subheadings
*Epidemiology seems brief relative to other sections-perhaps merge with a section or expand on this if possible
*Table in Diagnostic tests-great however an image would help break up the text
*Glossary could be extended further
*Referencing inconsistent
*Image/text ratio is good however layout could be improved
*Overall, a very informative and interesting page. Visual appeal could be worked on but once a few things are adjusted, it will finish it nicely
--[[User:Z3308965|Fleur McGregor]] 09:10, 29 September 2011 (EST)

Group 6

*Introduction is good and very clear, except there are no references, easily fixed but (Y)
*History could be incorporated into a table, or at least, the dates could be bolded or highlighted to establish progress through time.
*Good use of subheadings under ‘Signs and Symptoms’, might be beneficial to include more images as examples of each symptom, but just enough to provide a balance between text and images
*Genetics – well organised information, incorporation of images is excellent, many of the terms mentioned here could be defined in the glossary
*’Pathophysiology and Abnormalities’ – this section definitely needs to be referenced, but good info.
*’Treatment/Management’ – this table needs borders, i was easily confused as to which paragraph i was reading, but great info.
*Glossary could have a lot more terms included.

--[[User:Z3331469|z3331469]] 07:02, 29 September 2011 (EST)

'''Group 6 Peer Review'''

• Nice and simple sub-heading structure. I like the consistency of two images throughout the page. However I feel like you have lots of text with fewer images.

• Introduction is clear and to the point, however where are you references? And an image in this section is always good to give a representation of the abnormality from the start.

• History is really good! Clearly researched very well and good images! Interesting to read. However, the use of a timeline or ‘bolding’ all the dates would make it an easier read.

• Epidemiology is good, however I think you could elaborate more and possibly add a table/graph.

• I personally think that your signs and symptoms would look better displayed in a table. Definitely need more images here, possibly one for each sign/symptom.

• Why are signs and symptoms before the aetiology and pathogenesis of the disease? For me, it’s more logical to explain the cause and how the disease comes about before the signs and symptoms.

• Pathophysiology and abnormalities is a really good descriptive section. Well explained! And good use of images. But where are all the references?

• Diagnostics test has interesting information. Inconsistent referencing system to the entire page, also desperately in need of images to break up all that text.

• Future directions is well summarised, with relevant headings.

• Not really sure what’s going on with your referencing, but you need to have a consistent system throughout the entire page with no doubling up of articles.

--[[User:Z3289829|z3289829]] 02:44, 29 September 2011 (EST)

*Intro: Best not to start off the introduction with stats, people will quickly lose interest. I like how you’ve given a very brief idea of each subheading. This section would benefit from a picture , something to grab your attention.

*History: A timeline would be best, as this section isn’t as significant as the others so it doesn’t need to be in extensive detail.

*Epidemiology: “ It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered” repetitive. Best if not mentioned in introduction, as it is useful fact in this segment. Needs a little more detail, quite short in comparison to other sections.

*Signs and Symptoms: Good use of subheadings, need more images. Loved the audio! Very interesting. This section needs to come in after aetiology though.

*Genetics/Aetiology: Quite extensive, very detailed and understandable, but a lot longer than the other sections, it could do with a bit of trimming. Also the one type of image being used 3 times is not appealing, perhaps hand draw it in different colours or get a different style of drawing representing it.

*Pathophysiology: Like the subheadings and it’s easy to follow the information.The first image is great, the 2nd image could be broken down and hand drawn to compare the normal blood flow with TOF blood flow individually, instead of having the other conditions included. This would make it more clear.

*Diagnostic Test: Table is clearly incomplete. Add images, and add colour. The text is also not referenced. Why is there one reference at the bottom of the table?

*Treatment: Quite detailed and informative. There are many sections missing references above the table.

*Glossary: INCOMPLETE. There’s many more words you can add here.

*References: Links to other pages don’t count as references- that needs to be fixed.

*Overall: Great job. You’re image:text ratio is little unbalanced, as you need more interesting pictures. Needs a few changes here and there as I’ve mentioned above but it’s looking good so far.

--[[User:Z3290270|z3290270]] 02:29, 29 September 2011 (EST)

'''Peer Review'''
* Introduction needs more/any references.
* Use of a quote in History is interesting.
* History sections seems to be too focused on certain specific procedures rather than their significance for the disease itself and the patients.
* Some grammatical errors in various sections.
* Epidemiology seems a bit short...if no other details can be found for it, consider merging it with another section?
* Signs and Symptoms can use more references, but the subheadings used are very fitting and set out the information well.
* The subheadings in Genetics/Aetiology mean nothing to me. Explanations? On that note, the glossary can be more filled out.
* The layout of Genetics/Aetiology can probably be tweaked a bit.
* Pathophysiology is set out very nicely, but it needs references.
* The table in Diagnostic Tests is very succinct, but the section needs some text, if only to introduce/explain the table. Also, there is a random reference at the bottom.
* Treatment/Management needs more references. The table therein is strange, but the information is very well presented.
* The inclusion of a Prognosis section is interesting, but maybe consider putting it within Treatment/Management?
* Inclusion of Future Directions is very good but the references need to be cleaned up.
--[[User:Z3290689|z3290689]] 01:15, 29 September 2011 (EST)

Group 6
*Introduction: well summarised, but paragraphs don’t flow. This section needs referencing and a few terms could be defined in the glossary.
*History: good use of images to break up text. Maybe consider a timeline just to summarise the section since there is a lot of information here to digest.
*Signs & Symtoms: I like the use of subheadings – clearly indicates topics discussed. Maybe consider un-bolding the list of mumurs since they are not headings, just to keep the formatting consistent.
*Genetics: I like the images which are consistent throughout and the use of gene profiles – nice touch.
*Pathophysiology and abnormalities: well written & formatted section. Referencing?
*Treatment/Management: The only thing I would suggest is to add borders to the table so that the rows are clearly separated. I like the external links.
*Perhaps the page needs just a few more images/tables to break up the heavy text. And the glossary should be expanded.

--[[User:Z3332327|Lisa Xiao]] 00:48, 29 September 2011 (EST)

Group 6
Hey, nice progress with your page, all sections have similar amount of content which were interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Referencing needs to be improved here
#* History: content is good but too wordy. I think a summary or a simple timeline would be good
#* Epidemiology: Where's the reference for 3/10000 live births?
#* Signs: ok section, but could do with more images here
#* Genetics: If using abbreviations, such as TBX1 gene, you should explain what it is, ie. TBX1 gene (T-box 1). Also need to work on referencing here as well. How about organising all the content in a table? have in columns: gene, gene profile, frequency, etc.
#* Pathogenesis: I'm not quite sure about this, but do you need permission to adapt an image from an article? (I'm referring to the '4 defects' image)
#* Diagnosis: I'm sorry, but this section is a bit bland, though the content is very informative. I think some images here would be good
#* Treatment: Referencing! Also, personally, that green is too bright, maybe find a more neutral, soothing colour?
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to find more images, I feel some of the information could be more effectively presented in table formate rather than lengthy text
#Content is correctly cited and referenced.
#* VERY poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* research done is evident, just need to reference
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#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.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* glossary is very lacking in terminology
* need more images
* REFERENCING!

--[[User:Z3291643|z3291643]] 23:25, 28 September 2011 (EST)

'''GROUP 6:Tetralogy of Fallot'''
*Info in the intro is succinct and informative but sentence structuring and punctuation lets this down e.g. "These genetic mutations contribute to the four characteristic defects, in the heart of a patient having TOF" - comma is misplaced here
*"disease that occurs in 3 in every 10000 live births" -consider rephrasing this
*Intro needs an image to draw attention of reader
*While I appreciate the sectioning of the history section, i think that a chronological timeline may be more comprehensive for the reader, I feel that some of the dates are all over the place, also the history of this disease seams to stop at 1950s, could you maybe find more recent findings or contributions
*History images are good but need to be properly referenced and student template is missing from the first image
*I feel epidemiology section is a little underdeveloped, could you possibly find some more stats and compare incidence in several countries?
*Signs and symptoms has good info, but i feel that some sections could be expanded more
*signs and symptoms could use more images to accompany info
*I like the audio links to the heart signs
*Genetics/Aetiology section looks like it has been thoroughly researched, i like the structure of how each gene is dealt with, however, this info could be better formatted in a table and summarised a little more (if you are going to include all this technical info make sure it's explained in glossary maybe), also images in this section need better descriptions in the legends
*Pathophysiology and Abnormalities (I'm not sure if this is the best heading, could maybe be associated conditions or associated abnormalities or even just Cardiac abnormalities), info here is good but could be expanded a little more seeing as cardiac abnormalities seem to be a major manifestation of this anomaly
*Diagnostic tests section could be better placed further up? appears to have some info missing, and in some parts too much text, maybe could be summarised a little. Images could help break up the text, use of a table here is suitable but colour for the side headings could make it stand out a bit more. Referencing really needs to be fixed for this section
*Treatment and management is well researched, however Palliative Procedures could use more referencing esp. at the beginning. Table included is good but could be improved with colour and sectioning
*Prognosis has good inf but lacks referencing

Overall:
*More images are needed to balance out text
*Reference list needs work, don't think it's sufficient to just provide links to websites
*proof reading is needed to fix spelling mistakes, grammar issues and general sentence structure
*Glossary needs finishing, consider linking glossary words to the text and adding any acronyms used
*referencing of some images need to be fixed and student templates are missing in some

--[[User:Z3331556|z3331556]] 22:12, 28 September 2011 (EST)

'''Group 6'''

*The introduction is good but it would be better if there was some referencing.
*The history seemed abit chunky ? maybe a summarised version in a form of a timeline would be good. But overall the use of images is good, it breaks up the heavy text more.
*Epidemiology was abit too short, maybe expanding on why it is this pattern and etc would be a good idea.
*Signs and Symptoms had a nice summary of information. Maybe more pictures would make it more easy on the eyes because this section is quite big on the info. But the audio is a interesting idea!
*Genetics - Firstly, maybe get rid of mark's post. Secondly the layout of information is not that appealing, maybe you could underline the headings to make it more definite. Lastly, the use of images is good! it is very consistent for all genes.
*Diagnostic Tests section was not referenced! If it was then this section would be a winner, if it was completed!
*Overall, it looks like you guys have done alot of research. Good job!

--[[User:Z3330313|z3330313]] 00:01, 29 September 2011 (EST)

'''Group 6:'''

•Very text heavy, perhaps an image in the introduction could be added to grab the attention of the reader and create a better balance between text and images.

•Also, there are no references in the introduction. The source of this information needs to be references properly.

•The history section is worded well, though it may be more visually appealing and better formatted in a timeline. Also it seems to stop at the 1950s period. Is there no other recent research or developments made that could be added to bring the timeline up to date?

•The epidemiology section is quite short

•Good description of the signs and symptoms and good use of external links in this section for further information

•I like the diagnostic tests table, although it is incomplete at the moment, when the images and other information is added then this section will be very well done. Just make sure that it is referenced properly though, because it seems to be lacking referencing at the moment.

•Glossary needs to be completed and a number of the references are repeated

•Good work overall, some sections just need to be fixed up and completed and some more images added, but the overall formatting seems fine.

--[[User:Z3332183|z3332183]] 21:30, 28 September 2011 (EST)

'''Group 6'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there. History is well done, perhaps a time-line could be used?

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Good use of headings, subheadings in history was well used.

'''*Content is correctly cited and referenced.'''
File:Finger-Clubbing.jpg, File:TBX1.jpeg, File:NKX2-5.jpeg, File:JAG1.jpeg and File:Normal fetal blood flow and Tetralogy of Fallot.jpg should be referenced properly.

'''*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.'''
Well done student image with good explanation. More images would be good. Include more terms in glossary. Table in diagnostic tests has too much text. Table should be used to summarise, put main block of text outside of the table.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Prognosis needs more referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Good information in genetics, but maybe relate the symptoms to problems? (eg: what does Conotruncal anomaly face syndrome mean for the person/fetus?)

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has developed wiki according to guidelines but some changes could be good.

--z3329495 21:18, 28 September 2011 (EST)

'''Peer Assessment Group 6-Tetralogy of Fallot'''

* An image in 'Introduction' will make the beginning of the page more lucrative
* History might work better as a timeline, with bullet points and bold the dates so it is easier to follow.
* Surgical history and Contemporary History has a lot of information, some of it overlaps.The whole section could be replaced by a 'easy to follow' timeline. Good pictures in history.
* Are you going to expand on 'Epidemiology',? Maybe talk more about the actual pattern of occurrence rather than just a couple of observations from epidemiological studies?
* Are you also adding a description for Aortic Insufficency Murmur? The other three heart murmur types have an explanation except for this one.
*There are too many gaps in between the lines, makes the page look a bit sparse.
* Genetics looks quite full on. You may want to add more distinct subheadings to make it easier to follow and keep the reader's attention
* 'Abnormalities' looks great however you might want to change the italics to just bolded headings, makes the page look more consistent. Also make the numbers bold if you are going to have the text following the number bold.
* Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Even though the table is coming along make sure you take the reference off from the bottom of the table and add pictures. It looks like a work in progress. Also the referencing style is different to the rest of the page
* The student drawn pictures under treatment is nice.
* The table is also quite succinct
* 'Future directions' doesn't sound great as a heading. Use something more appropriate to the context
--[[User:Z3308968|Tahmina Lata]] 19:21, 28 September 2011 (EST)

'''Peer Assessment Gr 6'''
*History – what has been done in the last 50yrs? It seems to stop around 1950.
*Signs and symptoms- needs to be edited so it flows better, avoid long wordy sentences – just break them up into 2 (e.g abnormal growth part). Do you have a pic of a blue baby?
*Genetics- need a bit more space between each gene section, just to make it really clear (e.g. between the end of 5q34 and 20p12.1)
*Diagnostic tests table is good (but incomplete), perhaps consider using colours like other groups has? But the bright green of the shunt table is too bright, it hurts my eyes haha.
*References under the reference table needs to be fixed – do you want them to be in the table, or a list of them or what? Same for the references in the future directions section.
*Very well researched and thorough explanations
*Maybe expand the glossary?
*Reference section has some that double up (one after another) – there is a way to fix this and condense it.
*Do you have some photos of real hearts that have been affected by this disorder?
--[[User:Z3332824|z3332824]] 17:46, 28 September 2011 (EST)

'''Group 6: Peer Assessment'''
* It would be good to see more images
* The introduction would be more engaging if it had an image
* The history section is informative however would be nicer in a chronologic fashion. May be a table?
* The extra surgical history makes it clear that surgery plays an important role. Good
* Signs and Symptoms and genetic abnormalities are good overall. Many of the terms need to be added to the glossary though and it might be better to put aetiology first.
* It's a quite big and text heavy table in your diagnostic section. May be you can make it shorter, put pictures in

* I found quite a few words that should be in the glossary
* There is no title for your reference section and it looks like you should have more references for the amount of text that you have written
* Overall your page is very informative, good content. You need more images, appropriate referencing and a more complex glossary. --z3279511 17:11, 28 September 2011 (EST)

'''Group 6 Peer Review'''
* Good introduction, although an image straight up would be nice!
* History is presented well, although a table format at the end that summarises everything you have said would be nice. Also, does the history stop around the 1950's? It seems like there has been nothing done on it until 1970/1980? Hence, the table format would be nice if it appears that I've missed information.
* Epidemiology section is really quite short. Is there nothing more that can be said on it? Does it have preference to specific race?
* Signs and symptoms - from the way that the page is formatted it appears that you've gone down onto the level 4 headings with 4 ='s paraphrasing each heading. Try to use 3 or so just to make sur e the headings are larger and each subsection can be identified.
* The genetics/aetiology section should be explained better; whilst this is aimed at academics, it is almost impossible to understand the information pertaining to the genetics section.
* The pathophysiology and abnormalities section is well explained, and the diagram is excellent to show exactly where the problem lies. A well done section, and a well-selected image for the blood flow patterns.
* Diagnostic tests: Still need to insert those images on the right hand side column! Also, ensure that the referencing is done in the correct format - this section still needs work.
* Treatment/Management section is done well, with a good balance between text and table.
* Current and Future research: Perhaps more dates? The formatting here also needs to be fixed up, and try to have dates on the papers that you are quoting from (although I understand it's difficult without the references in place)
* The glossary section needs more terms added to it! Especially from the genetics/aetiology section which is already terribly difficult to understand.
* Referencing section is quite short - but understandably the whole project feels like the referencing just needs to be finished.
* Overall a nice-looking project with a lot of promise. The spacing and format of the project makes it easy to read - perhaps more images and the use of some tables might also assist in the presentation of this project.
--[[User:Z3288827|Leonard Tiong]] 10:49, 28 September 2011 (EST)

'''Group 6'''

*My first impression is that this project is lacking images. There is way too much text in comparison to images.
*An image would nicely complement the introduction
*I feel that history would work better in a timeline
*Epidemiology needs a table/graph
*Good links in signs/symptoms although another image would be nice
*Genetics needs to be explained a little better
*Student drawn images were great- obviously a lot of effort has been put into these
*Diagnostic test table needs an image and needs to be referenced properly
*Again, an image is needed for prognosis
*Glossary needs to be extended
*Overall a good project but you need to fix a few things

'''Group 6'''

*Introduction: the contend is ok, but the structure could be clearer

*History: too text heavy, a timeline would be nice

*Epidemiology: more content would be good

*Symptoms: the picture could be more general

*Genetics/ Aetiology: the structure could be better, maybe use some more subheadings, and put the gene profile in tables

*Pathophysiology: you need references

*Diagnostic tests: why does it say “insert images”, that should be fixed

*Treatment/ management: looks like there are some references missing? Deleate “Want to learn about more surgery and treatment methods?”, the contend is good, types of shunt would look better as a table

*Prognosis: references missing? good use of subheadings,

*Glossary: incomplete
--[[User:Z3387190|Z3387190]] 21:52, 27 September 2011 (EST)

'''Group 6 peer assessment'''
*Introduction is clear though lack images where a image of example of a blue baby would suffice
*History begins clearly though becomes about surgical history instead of the disease, where time line is not even present of how understanding of this disease improved.
*Epidemiology should be expanded either the genetics of the disease, in general have more information of the causes, incidence and distribution of the disease.
*Signs and symptoms poorly structured and requires more images also doesn’t have an introduction to the signs and symptoms. Although the extra links to comparison of the heart is useful and nicely used.
*Pathophysiology should add supplementary information to back up all the information.
*Diagnosis please add the images, while there is the content though no image following also first box has “insert text” very confusing.
*Treatment/management indicate the separation of surgery and other treatment types in the introduction which is lacking otherwise all is A ok
*Glossary needs to be referenced to other sections of the web page also expanded as most language used is unknown without a dictionary.
*Referencing needs to be fixed as links is not proper referencing also the repeats need to be removed
z3332250 23:53, 26 September 2011 (EST)

===Comments on Group Project 6===
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

--Z3389806 08:03, 26 September 2011 (EST)

'''Group 6 Critique'''

#• Introduction is ok, however it needs to be structured a lot better than what it is
#• History is interesting
#• Epidemiology needs a lot more detail. A few lines is not good enough
#• Signs and Symptoms is ok
#• Genetics needs to be explained a lot more clearly than what it is
#• Abnormalities is ok
#• Diagnostic tests table is impressive
#• Treatment/management section is very good
#• Prognosis and future directions section is great
#• Glossary is incomplete. Check the first term and fix this

--[[User:Z3289991|Robert Klein]] 19:05, 24 September 2011 (EST)

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

Group 6-
* No way near enough images. As I scrolled through there was HEAPS of text and only a few images, all of which are on the right hand side. It would be better if they were scattered around
* An image in the introduction would be helpful
* What are ‘tet spells’? mentioned in the introduction (described later but when seen in the introduction it looks like a typo)
* History would work better as a list of dates rather than paragraphs. I do like the section at the top with the quote though
* Epidemiology needs an image- perhaps a table or a graph.
* Signs and symptoms could do with another image to visualise the clinical manifestations
* I really liked the audio clips but the first one didn’t work on my computer? I couldn’t hear anything. Not sure if it was just me
* I think you can come up with a better way of formatting the genetics section. Maybe a table? The information is good it just looks a bit funny
* The pathogenesis doesn’t actually say HOW is happens in infants. Is this a condition formed during embryonic development or after?
* The diagnosis section is far from complete. This needs to be corrected
* Diagnosis section is also not referenced properly
* Why is there a reference at the bottom of the diagnosis section?
* As funny as this was: ‘Want to learn about more surgery and treatment methods? Check here!’…. maybe not appropriate sorry. It should be a little more formal. If you want the reader’s attention- try colour.
* Prognosis- image needed please. Maybe a graph?
* The glossary also needs to be extended
* The references need to be tidied up- there are also not many?
* You need to reference your images properly. ‘normal fetal blood flow and tetralogy of fallot’ is an example. You have but the copyright but not the reference. The web address is not a reference
* You are clearly on your way with the project but more work is required. You need to FINISH the content and format it a little better with more images.

''Group 6 Assessment'''
*First, I’d like to note good job on using a reference more than once in the correct way instead of referencing the same thing multiple times. At least this is done in the first few sections. First time I’ve seen this done correctly!
*The introduction, however, has no references whatsoever. Where did this information come from?
*It might also be good to add a simple picture in the introduction section so it looks more appealing.
*Good information included in the history section. It might look better if this were laid out in a bullet format though.
*The epidemiology section looks rather bland. Not only is there not a picture, but there also isn’t very much information included. Think about what else you could include here or what you could go into depth about.
*The signs and symptoms section has good information, but it might be a good idea to represent this information in a better format, possibly in a chart, with pictures of each symptom included in the chart.
*Finger-clubbing.jpg also needs a detailed description still.
*Good organization and format under the Genetics section.
*Under the pathyphysiology and Abnormalities section there are no references made. Where did this information come from? Diagnostic Tests and Treatment also needs more referencing.
*Pictures still haven’t been inserted into the Diagnostic Tests chart.
*More referencing is needed for the Prognosis section. Also, does the glossary terms need to be referenced?
*It would be a good idea also to 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. References 7-14 are the same reference. Fix these so they are under one single reference number.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Overall, there is a substantial amount of information given within this page, which is good. I like the basic format of everything and most of the pictures which are included. Just work on weaving everything together better and referencing things correctly. Good job!

--[[User:Z3391078|Z3391078]] 15:32, 27 September 2011 (EST)

'''Group 6'''
* Nice overall structure and good use of headings and subheading. It gives the page a nice flow.
* INtroduction is nice and straight to the point and gives the reader a good overview of your topic.
* I like the historical section with interesting subheadings used, maybe you could add a timeline just to simplify the info.
* Signs and symptoms nicely arranged. could you add some more pictures here?
* Pathophysiology and Abnormalities section need to have the references accompanying the information. Just so the read can identify where all the info is from.
* The diagnostic tests table would be nice with some colour and when the images are it will look complete. It's a little text heavy for a table maybe try bullet points. also the referencing system has changed in this table? and a little unsure of the reference at the bottom of the section?
* Treatment/Management section is nicely arranged.. could you add another picture here just to compensate for the amount of text. the table really brightens up the page!
* Future directions section is nicely summarised and I like the tone of voice used here. just make sure the referencing is correct as it is a little confusing and interrupts the flow of the section.
* Maybe the use of similar tables and colour scheme will increase the continuity of the page.
* Make sure your references are not doubled in the list.
* Ensure all of your pictures are correctly referenced.
* Make sure all acronyms and scientific wording is in the glossary.

*'''Intro''': What's a tet spell?
*'''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.
*'''Edidemiology''': Looks fine
*'''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.
*'''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).
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.
*'''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.
*'''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.
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.
*'''Glossary''': A bit poor. More technical terms need to be explained.
*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!

'''Peer Assessment: Group Project 6'''
*The introduction and the section on pathophysiology and abnormalities have no references. This needs to be rectified.
*The introduction and some of the history section have short paragraphs that are only one sentence long and would be improved, both for formatting and information purposes, by incorporating them into the rest of the information.
*Inserting a small timeline in the history section would make the sequence of events more accessible to the reader.
*Some sentences are too long such as, 'Children with TOF don’t grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth'. This sentence could be broken up and also improved by a greater explanation of why the process of growth is abnormal in TOF.
*Maybe explain more about what 'clubbing' is.
*In the diagnostic tests section the images need to be inserted and needs to be properly referenced. The information is good but as noted one section is totally void of text.
*The section on prognoses needs proper referencing.
*The section on future directions is well written, however the referencing needs to be adapted to the wiki format.
*Under the information in some of the images you have uploaded such as in the portait of A. Fallot, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The project is informative, however formatting and referencing are issues that need to be addressed.
--[[User:Z3217345|z3217345]] 22:23, 27 September 2011 (EST)

'''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.

--z3290815 20:31, 28 September 2011 (EST)

'''Peer Review'''

* really well done
* format and structure of the wikipage was consistent throughout

--[[User:Z3060621|z3060621]] 21:36, 28 September 2011 (EST)

Test:

{| style="color:black; background-color:#ffffcc;" width="85%" cellpadding="10%" cellpadding="15%" cellspacing="0" border="1"
| colspan="2" | '''Diagnosis'''
|}

--[[User:Z3291423|z3291423]] 11:57, 22 September 2011 (EST)

Hey Jaz, thanks for letting me know...my english can fail me at times.....lol...fixed it up... regards--[[User:Z3291317|Z3291317]] 18:49, 18 September 2011 (EST)

Hey guys! i just realised that the caption of helen taussig and ballot say portraight....not PORTRAIT!?!! i tried to change it but it don't really know how..anyone have any ideas to this?! :S thanks --[[User:Z3291423|z3291423]] 00:06, 17 September 2011 (EST)

Table Test! --[[User:Z3291423|z3291423]] 22:16, 16 September 2011 (EST)
{|
|-bgcolor="# 99FFFF"
| '''Type of Shunt'''
| '''Description'''
| '''Reasons for it not being used'''
| '''Image'''
|-
| Pott’s Shunt
| This shunt is a connection that is established between the lower part of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery.
| The shunt has a tendency to increase the pulmonary blood flow and it is also very hard to close when complete repair is undertaken
| Insert image
|-
| Waterston Shunt
| This shunt was placed between the back of the Aorta, to the right branch of the pulmonary.
| This shunt’s use is more suited to those with pulmonary artery stenosis and also the procedure is quite difficult to perform.
| Insert Image
|-
| Glenn Shunt
| The Super Vena Cava is anastomosed via a shunt to the right pulmonary artery.
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task.
| Insert image
|}

Table test (fingers crossed!) --[[User:Z3291324|Jacqueline Ellero]] 10:49, 15 September 2011 (EST)

==TOF diagnostic techniques==

{|border="1px" cellspacing="1" align="center" cellpadding="5" style="background:seashell"

|+ This table describes different diagnostic tests for TOF
! Diagnostic technique !! How the procedure works !! Presentation in TOF patient !! Image

|-
|Physical examination
|TOF is often diagnosed during fetal life by echocardiography (Apitz, Webb, & Redington, 2009). If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation. These signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with cyanosis and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. (Somerville, 1993)

|Insert text here
|Insert physical examination image
|-
|Heart murmurs
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh systolic ejection murmur may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). http://ccjm.org/content/77/11/821.full
|Insert heart murmur image
|-
|Electrocardiogram
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.(Somerville, 1993)
|Insert electrocardiogram image here
|-
|Chest radiograph
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnoses many conditions including the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. (Bailliard & Anderson, 2009) The radiograph will also show a right-sided aorta in approximately one-quarter of patients. (Somerville, 1993)
|Insert CXR image here
|-
|Echocardiogram
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. (Bailliard & Anderson, 2009)
|Insert echo image here
|-
|Magnetic resonance imaging
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect. (Somerville, 1993)
|Insert MRI image here
|-
|}

Hey peeps just put a intro just as a draft...tell me what you guys think of it. Edit it as you may wish.... And Jaq, if you describe briefly how each test works it would be good, regards --[[User:Z3291317|Z3291317]] 23:16, 14 September 2011 (EST)

hey jaz, ive fixed up the diagnosis, but feel free to add anything! or let me know if you think i should add anything. --[[User:Z3291324|z3291324]] 10:06, 14 September 2011 (EST) should i describe each diagnostic test!!??--[[User:Z3291324|z3291324]] 10:07, 14 September 2011 (EST)

Hey Guys! just added a very few changes, links etc to treatment. I've begun to add make a bit of notes on diagnosis that could just add a bit of detail to the diagnosis section. just wondered if any of you guys know what particular section of the ECG indicates...Left Ventricular Hypertrophy etc maybe ill call up a cardiologist :P nonetheless ill add references and some things to diagnosis tmrw night. regards, --[[User:Z3291423|z3291423]] 00:15, 14 September 2011 (EST)

Hey jaq. no particular order, the referencing system in the wiki automatically arranges it according to the order it is found in the text. In text referencing is NEEDED, lol. Type in the text title into Pubmed and when the article is found, the pmid code will be found at the bottom of the abstract for that article. if you cant figure out how to reference, put in the pubmed ids as intext citations then ill fix it for you...Make pathophys a bit more simpler, but do not compromise the anatomical words, i.e. write the anatomical word, then write in brackets what it means, eg. ''...anterolaterally (at the top away from the midline)'' is just an example (a crap one to lol). Also did you find any new info for diagnostic tests? and Rom, why did you remove info from the 22q section???? regards --[[User:Z3291317|Z3291317]] 22:02, 13 September 2011 (EST)

hey guys, quick question about the referencing. are they in any particular order? or should i just add mine to the end of the list? and do we need to do in-text referencing?? and how do you find the pmid code? also, any suggestions on how i should improve pathophys? ie make it more anatomical based or reword it so its simpler? thanks --[[User:Z3291324|z3291324]] 21:30, 13 September 2011 (EST)

Hey Rom, looking good thus far. if you need help with referencing even after trying so much i can help you during the 1 hour we have afta the lecture tomorrow to go through and help you fix em up... its a bit tricky but can get a handle of it... --[[User:Z3291317|Z3291317]] 20:37, 12 September 2011 (EST)

Hey guys sorry for the delay, but I'm slowly uploading all my stuff up. I'm just a bit confused about how I do the reference tag thing, as you can see there is a massive red thing on our reference list. I tried copying how you guys did it but I failed at it. I'll be posting some more in the next couple of hours, I just need to get a hang of this coding thing gah!
--[[User:Z3290841|z3290841]] 19:36, 12 September 2011 (EST)

hey rommel, we really need to see your part of the project and get your suggestions on parts we have done because its due on thursday --[[User:Z3291324|z3291324]] 19:16, 12 September 2011 (EST)

Hey Peeps, Just reconstucted the referencing so they are done exactly as it should be... Also just uploaded a pic of Mr fallot Himself without any copyright restrictions ( aha ow ye ow ye, took me long before i found it lol). I left the intext references jac and jaz put in their sections for future reference. Thats about it for now... Jaz i hope u liked the pics i showed you, and i hope rom is going well in his section... See yous soon... Regards --[[User:Z3291317|Z3291317]] 17:36, 11 September 2011 (EST)

update: uploaded the drawn images, took ages but its finally done :) and I've just finished the future directions :) so it should be fine to edit and look over in the next couple of days!
regards --[[User:Z3291423|z3291423]] 13:16, 11 September 2011 (EST)

looking good jaz. thanks for the articles fru. ive had a quick look at them but will need to fix it up after work this arvo! --[[User:Z3291324|z3291324]] 11:59, 11 September 2011 (EST)

Hey Jac, ive got 2 articles that i will send to your email, both talk about Cardiac Magnetic Resonance, one some detail about electrocardiography. Also, Jaz i have an article that has a section based on 'Future Innovations' for TOF, have a read and i reckon it will help out with the future directions part... i will send these articles to your emails so look at them when yous can... and rom, you breathing my friend?... regards --[[User:Z3291317|Z3291317]] 01:29, 11 September 2011 (EST)

hey guys, just reworded diagnosis so it makes sense. can anyone suggest any good articles to read for diagnosis? im having trouble accessing a lot of articles (they keep asking for passwords) and a lot of the articles dont discuss diagnosis in much detail at all. help is much appreciated!! thanks :) --[[User:Z3291324|z3291324]] 21:12, 10 September 2011 (EST)

hey rom, this might be helpful for genetics. not sure what youve got already though http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747103/
--[[User:Z3291324|z3291324]] 20:50, 10 September 2011 (EST)

also what should i do about the symptoms-pathophys overlap. should i alter the pathophys so its more anatomical like in the below article??--[[User:Z3291324|z3291324]] 20:10, 10 September 2011 (EST)

On to it now fru. thanks for the article. should i reword pathophys too so its easier to read/understand?--[[User:Z3291324|z3291324]] 20:08, 10 September 2011 (EST)

Hey Fru: in regards to the below comments, im working on future directions now :) also i read through the history section and it seems a lot more better :) just one mistake is the
"durng such operations there need". Ill have my edited prognosis and futures up by tonight! :) ohh and the heart! regards --[[User:Z3291423|z3291423]] 11:03, 10 September 2011 (EST)

Hey Jac i was reading the article: Review - Tetralogy of Fallot by Frederique Bailliard and Robert H Anderson ( im sure you have this one) and theres a section absed on " Anatomical variants of Tetralogy of Fallot, and associated anomalies". i believe if you could also include this section into the Pathophysiology section it would be great! Furthermore would you please do the things Mark said in regards to your sections it would be good, especially the diagnostic tests part :). Also to everyone we need to get Future Directions and especially Genetics up ASAP! thus respective people have them completed asap. --[[User:Z3291317|Z3291317]] 22:49, 9 September 2011 (EST)

Hey jaz, the prognosis sounds pretty good. maybe expand/explain how the hypoxic spells, brain abscesses etc cause death. i think in general we could expand upon most sections. off to work now guys but ill fix up my couple of sections tonight/tomorrow morn! --[[User:Z3291324|z3291324]] 08:30, 9 September 2011 (EST)

Thanks Fru! I will definitely crack onto those suggestions, I'm going to first email the owner of the children's hospital video on youtube to get permission for using the video, and then ill put it up in my section.
ALSO, I've nearly done the picture! I've got an outline and as your reading this, i should have it coloured, labelled and ready for upload! :D

have a great weekend guys!

Reagards
--[[User:Z3291423|z3291423]] 23:29, 8 September 2011 (EST)

Hey jaz just read your prognosis section. You made it well, however,i picked up 2 things you could do and it woould be good if you do them: 1. The causes of death after no surgery has done; if you can explain how these 'causes of death' occur due to TOF, it will portray the role TOF has in these problems. 2. You should talk about any complications that could arise in both patients that dont have corrected TOF and the ones who do have the surgery (i.e. any conditions that could develop after having the surgery or not, not just the death of the patient if they dont correct their heart). Other than that great work! :) --[[User:Z3291317|Z3291317]] 23:17, 8 September 2011 (EST)

Ye Jaz, thanks for the pic. Aswell ive attached a reviewed file of the treatment section on an email i sent to you. Maybe the youtube cideo based on the TOF fix up can now be put under this section as an embedded video... --[[User:Z3291317|Z3291317]] 22:19, 8 September 2011 (EST)

hey jaz, the treatment section is much better, much easier to read. thanks for the heart pic! im pretty sure my section is he one that is too "verbose" so anyone feel free to fix it up--[[User:Z3291324|z3291324]] 19:47, 8 September 2011 (EST)

Hey Guys! sorry prognosis took me a bit longer to do, but It will be up by tonight :) and ill upload the heart pic as well :) which took forever to make!
regards --[[User:Z3291423|z3291423]] 16:05, 8 September 2011 (EST)

hey guys just put up some diagnosis, let me know if you want me to add anything to it. furkan, glossary looks good! rommel, how are you going with the genetics do you need any help? and jaz are you able to post up the prognosis? once they are all up we should go through and edit them all together and fix up the wording. --[[User:Z3291324|z3291324]] 15:50, 8 September 2011 (EST)

Hey peoples...im going to start constucting the glossary wordbank as i read the entire document. Please add words yous think i missed out on... Also i found a pic of Mr Fallot but i think theres copyright rights on it. i think i gotta clear it somehow...--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

hey jaz, i think the treamtment section is alright. maybe reword the first bit into sentences (i think it was the bit on how severe the cyanosis is) so its a bit clearer. but otherwise good :) what do you think about pathophys?--[[User:Z3291324|z3291324]] 12:40, 7 September 2011 (EST)

hey guys, i cant tell if this pic has copyright or not. can someone please have a look for me? http://www.nhlbi.nih.gov/health/health-topics/topics/tof/ thanks!--[[User:Z3291324|z3291324]] 09:49, 6 September 2011 (EST)
--> REPLY: I looked at the pic and looks great. however, i couldnt see if it was copyright or not. HOWEVER, it is found on a public government website, and from what i remember Mark said we can use these materials. To make sure just please check it with him aswell. Also, im going to format your pathophysioligy section now so it looks prettier :)--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey guys, i Just finished the Treatment part, I've got palliative in this heading to still complete but Its very brief so i thought id get cracking on getting that drawing done and also the prognosis will be up by tomorrow! also check this out! http://www.nemours.org/content/dam/nemours/www/filebox/service/medical/cardiology/defect/tof.swf
--[[User:Z3291423|z3291423]] 23:57, 5 September 2011 (EST)
-->REPLY: Cool animation. Would we use an external link to this animation due to copyright restrictions?--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey Peepz

I just finished the sections of History, Signs and symptoms and Epidemiology

just please check these sections, especially the epidemiology one, do yous want it more detailed or is it enough?

z3291324 your section seems alright so far, show us your edited version so we can fully critic it then.

p.s. the post below my one i dont really understand itl who is speking to who and what are yous refering to? lol

Regards --[[User:Z3291317|Z3291317]] 23:44, 4 September 2011 (EST)

j: the article on future treatment directions sounds good. i might add some of the info in to the pathophysiology section because it links in well with the pulmonary stenosis and right ventricular hypertrophy. --[[User:Z3291324|z3291324]] 13:47, 2 September 2011 (EST)
I think this article makes some good points which could be added into the treatment section (eg discuss treatment/surgery after birth and also follow up treatments in adulthood- pulmonary valve replacement etc due to valvular incompetence and regurgitation because of the growing heart)

=pathophysiology=
hey guys. ive written some basic notes (UNEDITED) for pathophysiology. Just want to get an idea of how much detail i should go into before i start adding links to journal articles etc. can someone please have a quick look through and give me an idea of how much more detail is needed. thanks :)

The four features of tetralogy of fallot are pulmonary stenosis, overriding aorta, ventricular spetal defect and right ventricular hypertrophy. These features result from the anterosuperior displacement of the infundibular septum. The severity of symtpoms is determined by the extent of right ventricular outflow obstruction. 
'''Pulmonary stenosis'''
(Symptoms include cyanosis, right ventricular hypertrophy, hepatomegaly and peripheral oedema (of the legs). More mild symptoms include sudden fainting and dizziness from exercise. ) 
Valvular or infundibular stenosis (narrowing of the outflow tract of the right ventricle). Obstructs the outflow of blood from the right ventricle reducing pulmonary flow. If the pulmonary stenosis is mild, a left to right shunt (with no cyanosis) will form, due to the higher pressure in the left ventricle. However, significant pulmonary stenosis can raise right ventricular pressure above the left ventricular pressure and cause a right to left shunt (cyanosis etc). The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. 
'''Overriding aorta'''
The aortic valve has a biventricular connection. Instead of being positioned over the left ventricle, the aortic valve is located above the interventricular spetal defect allowing blood from both the right and left ventricles to pass through the aortic valve. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. Because the right ventricle receieves deoxygenated blood from the systemic circulation, the percent oxygenation of bloood entering the aorta and hence back into the systemic circulation is decreased. 
'''Ventricular septal defect'''
The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. During ventricular contraction, blood from the left ventricle passes into the right ventricle and then re-enters the pulmonary circulation. Leakage of blood from the left to right ventricle raises the right ventricular volume and pressure resulting in pulmonary hypertension. (Shortness of breath, dizziness and fainting) If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience cyanosis and deoxygenated blood is by-passing the lungs and entring the systemic circulation. (also breathlessness, poor feeding and failure to thrive in infancy.) 
'''Rigth ventricular hypertrophy'''
Compensatory response to pulmonary stenosis ...to be contined.

--[[User:Z3291324|z3291324]] 13:38, 2 September 2011 (EST)

=link to pathology textbook=

hey guys, this is the link to tetralogy of fallot in robbins pathology
--[[User:Z3291324|z3291324]] 13:05, 2 September 2011 (EST)

=More genetics and Surgery=

Hey Peeps, i forund another article in regards to Genetics as it does an genotype-phenotype anaylis os TOF Patients. Have a read and see if it can help in the assignment subsection. if you cant get the full article tell me and ill give you the pdf of it.

Article: PMID: 19948535

And Regards to surgery and its prognosis post-operation i found these articles that may be helpful for 3291423. Again if yous cant find the pdf tell me and i'll send yous the pdf articles of these.

Articles: PMID: 20091166 ; PMID: 21769263 ; PMID: 21566339 (hey 3291423 this is the article i showed you in the lab and you wanted it from me)

Anyways peeps i hope all the assignments are coming along well

Regards --[[User:Z3291317|Z3291317]] 19:03, 1 September 2011 (EST)

REPLY: Thanks z3291317, I had a look through the files and am using them now for summarising :) also, can you send through the picture of what you want the abnormal TOF heart to look like and ill get cracking on it to produce/draw it :)

regards --[[User:Z3291423|z3291423]] 22:15, 1 September 2011 (EST)

=Genetics=
Hey guys, found some articles relating to genetics and the deletion of the 22q11 gene. take a look :)
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

AS Bassett, EWC Chow and J Husted et al., Clinical features of 78 adults with 22q11 deletion syndrome, Am J Med Genet 138 (2005), pp. 307–313. http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science?_ob=MiamiImageURL&_imagekey=B6T18-3V8RDDJ-11-1&_cdi=4884&_user=37161&_pii=S0735109798002599&_check=y&_origin=&_coverDate=08%2F31%2F1998&view=c&wchp=dGLbVlW-zSkWz&md5=0a4f32c3b75ebff2513309081ac0468f&ie=/sdarticle.pdf

http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

=Treatment and future directions info/readings=

Hey guys, found this really amazing article about treatments and their repercussions http://www.ccjm.org/content/77/11/821.long#abstract-3
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

=Online lab 4 info=
I my friends , colleagues and countrymen am going to be undertaking the research of the subsection Genetics/Aetiology in the topics that have been discussed. --[[User:Z3290841|z3290841]] 10:18, 25 August 2011 (EST)

Im going to be researching Treatment/Management, Prognosis & Future directions. - z3291423

regards, --[[User:Z3291423|z3291423]] 23:30, 24 August 2011 (EST)

Thanks for typing them up. I'm going to research Pathophysiology and abnormalities and diagnostic tests.
--[[User:Z3291324|z3291324]] 15:40, 24 August 2011 (EST)

Hey Group 6

From the Meeting on Tuesday after the Embryo lecture, we had concluded that we are going to divide the group project of TOF into the following sub-sections (if i am not mistaken):

* Introduction
* History
* Epidemiology
* Signs and Symptoms
* Genetics/Aetiology
* Pathopgysiology and Abnormalities
* Diagnostic Tests
* Treatment/Management
* Prognosis
* Future Directions
* Glossary
* References

From these subsections, I (z3291317) will research the History, Epidemiology and Signs & Symptoms subsections of the group Project.

Just wanted to put forward my part for the group project :)

Regards --[[User:Z3291317|Z3291317]] 15:01, 24 August 2011 (EST)

=Resources=
Hey Group 6

When i was looking around for info in regards to TOF, i found some videos on youtube made by an american hospital which we could use on our page in the "more info" section. Check them out and tell me what yous think...

- http://www.youtube.com/watch?v=ACRfFkxow7w
- http://www.youtube.com/watch?v=jgLC2QABcxo

So what you guys think? --[[User:Z3291317|Z3291317]] 22:54, 21 August 2011 (EST)

COMMENT: great stuff! that really is a great tool, maybe we can incorporate that in as a link, or something to really explain it! without all the mumbo jumbo :) --[[User:Z3291423|z3291423]] 22:22, 22 August 2011 (EST)

=Articles=

Found really good article detailing some clinical aspects http://journals.cambridge.org.wwwproxy0.library.unsw.edu.au/action/displayAbstract?fromPage=online&aid=331031 its called: The clinical anatomy of tetralogy of Fallot, http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0140673609606577 - Tetraology of ballot by christian apitz, just google scholar it via unsw or use the link I've given you :) --[[User:Z3291423|z3291423]] 19:10, 20 August 2011 (EST)

=Images=
Hey guys, this is an image of tetralogy of fallot with pulmonary atresia

[[File: Tetralogy of Fallot with pulmonary atresia.jpg]]
--[[User:Z3291324|z3291324]] 22:07, 17 August 2011 (EST)

Hey guys, just found this still frame showing large ventricular septal defect, aortic override, and right ventricular hypertrophy which are all very common to patients with ToF
[[File:Some common effects for patients with Tetralogy of Fallot.jpg]]
--[[User:Z3291423|z3291423]] 21:43, 17 August 2011 (EST)

Hey guys this is my image of our disease, it is just outlining some of the basic changes that happens to the heart, mainly the right ventricle.

[[File:Right ventricle of heart with Tetralogy of Fallot.jpg]]

--[[User:Z3290841|z3290841]] 13:42, 17 August 2011 (EST)

----

Hey Group 6, its z3291317

I just wanted to make it clear that we add all new entries into our discussion page at the top of the page and not at the bottom of it. Thats how we are told to edit this discussion page.

Anyways this is my Image for Lab 3 Question 2:

[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg]]

I hope it would be beneficial for our page...

--[[User:Z3291317|Z3291317]] 12:05, 17 August 2011 (EST)

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)
Hey Group 6

i just done some research on a possible group project subject. It is quite detailed and interesting (to me) disease to write on.What do you guys think? Here is the review and research article for it:

The Disease:'''Tetralogy of Fallot'''

Review Article:

Orphanet J Rare Dis. 2009 Jan 13;4:2.

'''''Tetralogy of Fallot.'''''

Bailliard F, Anderson RH.

North Carolina Children's Heart Center, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. frederique_bailliard@med.unc.edu

Link: <ref><pubmed>19144126</pubmed></ref>

Description: This paper gives an overview about the disease, how it happens, and clinical manifestations.

Research Article:

J Med Genet. 2010 May;47(5):321-31. Epub 2009 Nov 30.

'''''Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.'''''

Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U, Hoyer J, Kaulitz R, Singer H, Rauch A.

Institute of Medical Genetics, Schorenstrasse 16, CH-8603 Zurich-Schwerzenbach, Switzerland. anita.rauch@medgen.uzh.ch

Link: <ref><pubmed>19948535</pubmed></ref>

Description: A study was done to see the prevalent phenotype for Tetralogy of fallot, and it was found that the 22q11.2 deletion was the most common type in Tetralogy of Fallot.

'''''References:'''''

<references/>

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)

----

--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

Hey Guys,

I did research on Cystic fibrosis and these are the 2 articles that I found that explains a lot about the disease, and the genetic research on it.

Review Article:

'''Cystic Fibrosis: Seminar'''

Description: This is basically outlining the pathophysiology of the disease, disease manifestation,current treatments diagnostic tool.

Ratjen F & Doring G.(2003).Cystic Fibrosis: Seminar.''The Lancet'', 361, 681-9. Retrieved from http://www.sciencedirect.com/science/article/pii/S0140673603125676

Research Article:

'''Gene expression profile study in CFTR mutated bronchial cell lines'''

Description: This article provides information about the severity of gene expression in relation of the extent or type of mutation.

Gambardella S, Biancolella M, D'Apice M, Amati F, Sangiuolo F, Farcomenti A, Chillemi G, Bueno S, Desideri A & Novelli G.(2006).Gene expression profile study in CFTR mutated bronchial cell lines.''Clinical and Experimental Medicine '', 6, 157-65. Retrieved from http://proquest.umi.com/pqdlink?Ver=1&Exp=08-05-2016&FMT=7&DID=1187181501&RQT=309&cfc=1

--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

--[[User:Z3291324|z3291324]] 20:48, 10 August 2011 (EST)

Hey guys, I like the disease that Furkan found (tetralogy of fallot)! What does everyone think?

These are the two articles I found. The review article gives a pretty good description of the disease, symptoms, treatment and complications etc. The research article looks at some of the genetic causes.

Goldmuntz, E., Geiger, E., & Benson, D. W. (2001). NKX2.5 mutations in patients with tetralogy of fallot. Circulation, 104(21), 2565-2568.

Apitz, C., Webb, G. D., & Redington, A. N. (2009). Tetralogy of Fallot. Lancet, 374(9699), 1462-1471.

Hey kiddes just done some research! check it out, its about Hypoplastic left heart syndrome

Review article:

2001 May-Jun;21(3):705-17.
'''Hypoplastic left heart syndrome.'''
Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP.

Link: [http://www.ncbi.nlm.nih.gov/pubmed/11353117]

Research:

2011 Aug 1;108(3):421-7. Epub 2011 May 31.
'''Prenatal diagnosis of hypoplastic left heart syndrome in current era.'''
Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ.
Link: [http://www.ncbi.nlm.nih.gov/pubmed/21624547]

References
<references/>
1. Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP ""Hypoplastic left heart syndrome.""Radiographics. 2001 May-Jun;21(3):705-17 <ref><pubmed>11353117</pubmed></ref>

2. Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ ""Prenatal diagnosis of hypoplastic left heart syndrome in current era."" Am J Cardiol. 2011 Aug 1;108(3):421-7. Epub 2011 May 31 <ref><pubmed>21624547</pubmed></ref>

==Peer Assessments==
* I would suggest placing the history section into a timeline or table format just so that significant dates are more clear and emphasised.
* The gene profile section was great. It was in detail, it was coherent and the inclusion of gene images enhanced my understanding of this particular section.
* Maybe for the “how the procedure works” section of the diagnostics table could have been summarised into a flow diagram or through images, rather than having a chunk of text. This could make it more straight forward to the reader.
* Your website was generally well-written and to the point. You varied your formatting regularly which made your page entertaining.
* My last suggestion would to only use the image of the shunt once and finding a different image as the repetitiveness of this is slightly disengaging
--[[User:Z3332629|z3332629]] 15:26, 22 September 2011 (EST)

User:Z3290618

2011-09-29T00:41:57Z

Z3290618: /* Lab Eight */

Talk:2011 Group Project 6

2011-09-29T00:41:56Z

Z3290618:

[[2011_Group_Project_6|'''Group 6''']]: [[User:z3290841]] | [[User:z3291317]] | [[User:z3291324]] | [[User:z3291423]]

{{2011GroupDiscussionMH}}

==Peer Review==

'''Peer Review'''
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)
Group 6:

Great intro, brief but covers everything. Good amount of references for the information provided
Genetics part was covered well.

The reference under diagnostic techniques should be with the other references and hopefully, by the end of semester there will be images where it says “insert images”

Good use of tables.

Maybe a few more pictures and the page will be perfect.

Evidently there’s been good work put in and the information has been researched well.

9-13 are all the one link so it should be one link not 5 separate links.

Clear and concise

z3332178 =]

'''Peer Review'''

*Introduction: the layout is a bit messy. Maybe get rid of the double spacing. It might also be a good idea to include an image e.g. maybe of a heart. Needs to include more references in this section.
*History section was well written. I suggest putting the quote in a blue box or highlighting it in some way to make it stand out. Try including a table or timeline to summarise the key events and findings.
*Signs and symptoms; Good layout and presentation of information. Easy to follow and understand.
*Genetics: shows it has been thoroughly researched. Like the use of images to compliment the text. Try and put the information in a table. The section is too lengthy in comparison with the other sections. Needs to hyperlink certain technical words to the glossary.
*Pathophysiology: well written. The information is concise and easy to understand. Good use of student drawn images.
*Great idea summarizing the information on 'diagnostic tests' in a table. Get rid of the in text referencing in the table.
*Add a border around the table in the treatment/management section.
*Other sections; good information. The referencing need to be fixed, it's not consistent. Try and include more images or tables in the prognosis, future directions sections to break up the heavy text. These sections seem a bit mundane compared with the rest. Prognosis section required more referencing.
*Glossary; need to be expanded.
--[[User:Z3291622|Z3291622]] 10:06, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*Introduction does not flow very well. Sentences are very choppy.

:*History section would benefit from a timeline rather than paragraphs as it is a bit hard to follow.

:*In the epidemiology and symptoms sections need some more content. Seems very minimal. Also images?

:*Diagnostic section needs the rest of the information added to its table. “Insert text here”. Also use of bolding or different font sizes would benefit this table.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:19, 29 September 2011 (EST)

Group 6 Peer Review

*Majority of page is in a logical and organised manner however maybe switch aetiology and signs and symptoms to make it flow better?
*History section had good, clear subheadings
*Epidemiology seems brief relative to other sections-perhaps merge with a section or expand on this if possible
*Table in Diagnostic tests-great however an image would help break up the text
*Glossary could be extended further
*Referencing inconsistent
*Image/text ratio is good however layout could be improved
*Overall, a very informative and interesting page. Visual appeal could be worked on but once a few things are adjusted, it will finish it nicely
--[[User:Z3308965|Fleur McGregor]] 09:10, 29 September 2011 (EST)

Group 6

*Introduction is good and very clear, except there are no references, easily fixed but (Y)
*History could be incorporated into a table, or at least, the dates could be bolded or highlighted to establish progress through time.
*Good use of subheadings under ‘Signs and Symptoms’, might be beneficial to include more images as examples of each symptom, but just enough to provide a balance between text and images
*Genetics – well organised information, incorporation of images is excellent, many of the terms mentioned here could be defined in the glossary
*’Pathophysiology and Abnormalities’ – this section definitely needs to be referenced, but good info.
*’Treatment/Management’ – this table needs borders, i was easily confused as to which paragraph i was reading, but great info.
*Glossary could have a lot more terms included.

--[[User:Z3331469|z3331469]] 07:02, 29 September 2011 (EST)

'''Group 6 Peer Review'''

• Nice and simple sub-heading structure. I like the consistency of two images throughout the page. However I feel like you have lots of text with fewer images.

• Introduction is clear and to the point, however where are you references? And an image in this section is always good to give a representation of the abnormality from the start.

• History is really good! Clearly researched very well and good images! Interesting to read. However, the use of a timeline or ‘bolding’ all the dates would make it an easier read.

• Epidemiology is good, however I think you could elaborate more and possibly add a table/graph.

• I personally think that your signs and symptoms would look better displayed in a table. Definitely need more images here, possibly one for each sign/symptom.

• Why are signs and symptoms before the aetiology and pathogenesis of the disease? For me, it’s more logical to explain the cause and how the disease comes about before the signs and symptoms.

• Pathophysiology and abnormalities is a really good descriptive section. Well explained! And good use of images. But where are all the references?

• Diagnostics test has interesting information. Inconsistent referencing system to the entire page, also desperately in need of images to break up all that text.

• Future directions is well summarised, with relevant headings.

• Not really sure what’s going on with your referencing, but you need to have a consistent system throughout the entire page with no doubling up of articles.

--[[User:Z3289829|z3289829]] 02:44, 29 September 2011 (EST)

*Intro: Best not to start off the introduction with stats, people will quickly lose interest. I like how you’ve given a very brief idea of each subheading. This section would benefit from a picture , something to grab your attention.

*History: A timeline would be best, as this section isn’t as significant as the others so it doesn’t need to be in extensive detail.

*Epidemiology: “ It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered” repetitive. Best if not mentioned in introduction, as it is useful fact in this segment. Needs a little more detail, quite short in comparison to other sections.

*Signs and Symptoms: Good use of subheadings, need more images. Loved the audio! Very interesting. This section needs to come in after aetiology though.

*Genetics/Aetiology: Quite extensive, very detailed and understandable, but a lot longer than the other sections, it could do with a bit of trimming. Also the one type of image being used 3 times is not appealing, perhaps hand draw it in different colours or get a different style of drawing representing it.

*Pathophysiology: Like the subheadings and it’s easy to follow the information.The first image is great, the 2nd image could be broken down and hand drawn to compare the normal blood flow with TOF blood flow individually, instead of having the other conditions included. This would make it more clear.

*Diagnostic Test: Table is clearly incomplete. Add images, and add colour. The text is also not referenced. Why is there one reference at the bottom of the table?

*Treatment: Quite detailed and informative. There are many sections missing references above the table.

*Glossary: INCOMPLETE. There’s many more words you can add here.

*References: Links to other pages don’t count as references- that needs to be fixed.

*Overall: Great job. You’re image:text ratio is little unbalanced, as you need more interesting pictures. Needs a few changes here and there as I’ve mentioned above but it’s looking good so far.

--[[User:Z3290270|z3290270]] 02:29, 29 September 2011 (EST)

'''Peer Review'''
* Introduction needs more/any references.
* Use of a quote in History is interesting.
* History sections seems to be too focused on certain specific procedures rather than their significance for the disease itself and the patients.
* Some grammatical errors in various sections.
* Epidemiology seems a bit short...if no other details can be found for it, consider merging it with another section?
* Signs and Symptoms can use more references, but the subheadings used are very fitting and set out the information well.
* The subheadings in Genetics/Aetiology mean nothing to me. Explanations? On that note, the glossary can be more filled out.
* The layout of Genetics/Aetiology can probably be tweaked a bit.
* Pathophysiology is set out very nicely, but it needs references.
* The table in Diagnostic Tests is very succinct, but the section needs some text, if only to introduce/explain the table. Also, there is a random reference at the bottom.
* Treatment/Management needs more references. The table therein is strange, but the information is very well presented.
* The inclusion of a Prognosis section is interesting, but maybe consider putting it within Treatment/Management?
* Inclusion of Future Directions is very good but the references need to be cleaned up.
--[[User:Z3290689|z3290689]] 01:15, 29 September 2011 (EST)

Group 6
*Introduction: well summarised, but paragraphs don’t flow. This section needs referencing and a few terms could be defined in the glossary.
*History: good use of images to break up text. Maybe consider a timeline just to summarise the section since there is a lot of information here to digest.
*Signs & Symtoms: I like the use of subheadings – clearly indicates topics discussed. Maybe consider un-bolding the list of mumurs since they are not headings, just to keep the formatting consistent.
*Genetics: I like the images which are consistent throughout and the use of gene profiles – nice touch.
*Pathophysiology and abnormalities: well written & formatted section. Referencing?
*Treatment/Management: The only thing I would suggest is to add borders to the table so that the rows are clearly separated. I like the external links.
*Perhaps the page needs just a few more images/tables to break up the heavy text. And the glossary should be expanded.

--[[User:Z3332327|Lisa Xiao]] 00:48, 29 September 2011 (EST)

Group 6
Hey, nice progress with your page, all sections have similar amount of content which were interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Referencing needs to be improved here
#* History: content is good but too wordy. I think a summary or a simple timeline would be good
#* Epidemiology: Where's the reference for 3/10000 live births?
#* Signs: ok section, but could do with more images here
#* Genetics: If using abbreviations, such as TBX1 gene, you should explain what it is, ie. TBX1 gene (T-box 1). Also need to work on referencing here as well. How about organising all the content in a table? have in columns: gene, gene profile, frequency, etc.
#* Pathogenesis: I'm not quite sure about this, but do you need permission to adapt an image from an article? (I'm referring to the '4 defects' image)
#* Diagnosis: I'm sorry, but this section is a bit bland, though the content is very informative. I think some images here would be good
#* Treatment: Referencing! Also, personally, that green is too bright, maybe find a more neutral, soothing colour?
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to find more images, I feel some of the information could be more effectively presented in table formate rather than lengthy text
#Content is correctly cited and referenced.
#* VERY poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* research done is evident, just need to reference
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#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.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* glossary is very lacking in terminology
* need more images
* REFERENCING!

--[[User:Z3291643|z3291643]] 23:25, 28 September 2011 (EST)

'''GROUP 6:Tetralogy of Fallot'''
*Info in the intro is succinct and informative but sentence structuring and punctuation lets this down e.g. "These genetic mutations contribute to the four characteristic defects, in the heart of a patient having TOF" - comma is misplaced here
*"disease that occurs in 3 in every 10000 live births" -consider rephrasing this
*Intro needs an image to draw attention of reader
*While I appreciate the sectioning of the history section, i think that a chronological timeline may be more comprehensive for the reader, I feel that some of the dates are all over the place, also the history of this disease seams to stop at 1950s, could you maybe find more recent findings or contributions
*History images are good but need to be properly referenced and student template is missing from the first image
*I feel epidemiology section is a little underdeveloped, could you possibly find some more stats and compare incidence in several countries?
*Signs and symptoms has good info, but i feel that some sections could be expanded more
*signs and symptoms could use more images to accompany info
*I like the audio links to the heart signs
*Genetics/Aetiology section looks like it has been thoroughly researched, i like the structure of how each gene is dealt with, however, this info could be better formatted in a table and summarised a little more (if you are going to include all this technical info make sure it's explained in glossary maybe), also images in this section need better descriptions in the legends
*Pathophysiology and Abnormalities (I'm not sure if this is the best heading, could maybe be associated conditions or associated abnormalities or even just Cardiac abnormalities), info here is good but could be expanded a little more seeing as cardiac abnormalities seem to be a major manifestation of this anomaly
*Diagnostic tests section could be better placed further up? appears to have some info missing, and in some parts too much text, maybe could be summarised a little. Images could help break up the text, use of a table here is suitable but colour for the side headings could make it stand out a bit more. Referencing really needs to be fixed for this section
*Treatment and management is well researched, however Palliative Procedures could use more referencing esp. at the beginning. Table included is good but could be improved with colour and sectioning
*Prognosis has good inf but lacks referencing

Overall:
*More images are needed to balance out text
*Reference list needs work, don't think it's sufficient to just provide links to websites
*proof reading is needed to fix spelling mistakes, grammar issues and general sentence structure
*Glossary needs finishing, consider linking glossary words to the text and adding any acronyms used
*referencing of some images need to be fixed and student templates are missing in some

--[[User:Z3331556|z3331556]] 22:12, 28 September 2011 (EST)

'''Group 6'''

*The introduction is good but it would be better if there was some referencing.
*The history seemed abit chunky ? maybe a summarised version in a form of a timeline would be good. But overall the use of images is good, it breaks up the heavy text more.
*Epidemiology was abit too short, maybe expanding on why it is this pattern and etc would be a good idea.
*Signs and Symptoms had a nice summary of information. Maybe more pictures would make it more easy on the eyes because this section is quite big on the info. But the audio is a interesting idea!
*Genetics - Firstly, maybe get rid of mark's post. Secondly the layout of information is not that appealing, maybe you could underline the headings to make it more definite. Lastly, the use of images is good! it is very consistent for all genes.
*Diagnostic Tests section was not referenced! If it was then this section would be a winner, if it was completed!
*Overall, it looks like you guys have done alot of research. Good job!

--[[User:Z3330313|z3330313]] 00:01, 29 September 2011 (EST)

'''Group 6:'''

•Very text heavy, perhaps an image in the introduction could be added to grab the attention of the reader and create a better balance between text and images.

•Also, there are no references in the introduction. The source of this information needs to be references properly.

•The history section is worded well, though it may be more visually appealing and better formatted in a timeline. Also it seems to stop at the 1950s period. Is there no other recent research or developments made that could be added to bring the timeline up to date?

•The epidemiology section is quite short

•Good description of the signs and symptoms and good use of external links in this section for further information

•I like the diagnostic tests table, although it is incomplete at the moment, when the images and other information is added then this section will be very well done. Just make sure that it is referenced properly though, because it seems to be lacking referencing at the moment.

•Glossary needs to be completed and a number of the references are repeated

•Good work overall, some sections just need to be fixed up and completed and some more images added, but the overall formatting seems fine.

--[[User:Z3332183|z3332183]] 21:30, 28 September 2011 (EST)

'''Group 6'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there. History is well done, perhaps a time-line could be used?

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Good use of headings, subheadings in history was well used.

'''*Content is correctly cited and referenced.'''
File:Finger-Clubbing.jpg, File:TBX1.jpeg, File:NKX2-5.jpeg, File:JAG1.jpeg and File:Normal fetal blood flow and Tetralogy of Fallot.jpg should be referenced properly.

'''*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.'''
Well done student image with good explanation. More images would be good. Include more terms in glossary. Table in diagnostic tests has too much text. Table should be used to summarise, put main block of text outside of the table.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Prognosis needs more referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Good information in genetics, but maybe relate the symptoms to problems? (eg: what does Conotruncal anomaly face syndrome mean for the person/fetus?)

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has developed wiki according to guidelines but some changes could be good.

--z3329495 21:18, 28 September 2011 (EST)

'''Peer Assessment Group 6-Tetralogy of Fallot'''

* An image in 'Introduction' will make the beginning of the page more lucrative
* History might work better as a timeline, with bullet points and bold the dates so it is easier to follow.
* Surgical history and Contemporary History has a lot of information, some of it overlaps.The whole section could be replaced by a 'easy to follow' timeline. Good pictures in history.
* Are you going to expand on 'Epidemiology',? Maybe talk more about the actual pattern of occurrence rather than just a couple of observations from epidemiological studies?
* Are you also adding a description for Aortic Insufficency Murmur? The other three heart murmur types have an explanation except for this one.
*There are too many gaps in between the lines, makes the page look a bit sparse.
* Genetics looks quite full on. You may want to add more distinct subheadings to make it easier to follow and keep the reader's attention
* 'Abnormalities' looks great however you might want to change the italics to just bolded headings, makes the page look more consistent. Also make the numbers bold if you are going to have the text following the number bold.
* Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Even though the table is coming along make sure you take the reference off from the bottom of the table and add pictures. It looks like a work in progress. Also the referencing style is different to the rest of the page
* The student drawn pictures under treatment is nice.
* The table is also quite succinct
* 'Future directions' doesn't sound great as a heading. Use something more appropriate to the context
--[[User:Z3308968|Tahmina Lata]] 19:21, 28 September 2011 (EST)

'''Peer Assessment Gr 6'''
*History – what has been done in the last 50yrs? It seems to stop around 1950.
*Signs and symptoms- needs to be edited so it flows better, avoid long wordy sentences – just break them up into 2 (e.g abnormal growth part). Do you have a pic of a blue baby?
*Genetics- need a bit more space between each gene section, just to make it really clear (e.g. between the end of 5q34 and 20p12.1)
*Diagnostic tests table is good (but incomplete), perhaps consider using colours like other groups has? But the bright green of the shunt table is too bright, it hurts my eyes haha.
*References under the reference table needs to be fixed – do you want them to be in the table, or a list of them or what? Same for the references in the future directions section.
*Very well researched and thorough explanations
*Maybe expand the glossary?
*Reference section has some that double up (one after another) – there is a way to fix this and condense it.
*Do you have some photos of real hearts that have been affected by this disorder?
--[[User:Z3332824|z3332824]] 17:46, 28 September 2011 (EST)

'''Group 6: Peer Assessment'''
* It would be good to see more images
* The introduction would be more engaging if it had an image
* The history section is informative however would be nicer in a chronologic fashion. May be a table?
* The extra surgical history makes it clear that surgery plays an important role. Good
* Signs and Symptoms and genetic abnormalities are good overall. Many of the terms need to be added to the glossary though and it might be better to put aetiology first.
* It's a quite big and text heavy table in your diagnostic section. May be you can make it shorter, put pictures in

* I found quite a few words that should be in the glossary
* There is no title for your reference section and it looks like you should have more references for the amount of text that you have written
* Overall your page is very informative, good content. You need more images, appropriate referencing and a more complex glossary. --z3279511 17:11, 28 September 2011 (EST)

'''Group 6 Peer Review'''
* Good introduction, although an image straight up would be nice!
* History is presented well, although a table format at the end that summarises everything you have said would be nice. Also, does the history stop around the 1950's? It seems like there has been nothing done on it until 1970/1980? Hence, the table format would be nice if it appears that I've missed information.
* Epidemiology section is really quite short. Is there nothing more that can be said on it? Does it have preference to specific race?
* Signs and symptoms - from the way that the page is formatted it appears that you've gone down onto the level 4 headings with 4 ='s paraphrasing each heading. Try to use 3 or so just to make sur e the headings are larger and each subsection can be identified.
* The genetics/aetiology section should be explained better; whilst this is aimed at academics, it is almost impossible to understand the information pertaining to the genetics section.
* The pathophysiology and abnormalities section is well explained, and the diagram is excellent to show exactly where the problem lies. A well done section, and a well-selected image for the blood flow patterns.
* Diagnostic tests: Still need to insert those images on the right hand side column! Also, ensure that the referencing is done in the correct format - this section still needs work.
* Treatment/Management section is done well, with a good balance between text and table.
* Current and Future research: Perhaps more dates? The formatting here also needs to be fixed up, and try to have dates on the papers that you are quoting from (although I understand it's difficult without the references in place)
* The glossary section needs more terms added to it! Especially from the genetics/aetiology section which is already terribly difficult to understand.
* Referencing section is quite short - but understandably the whole project feels like the referencing just needs to be finished.
* Overall a nice-looking project with a lot of promise. The spacing and format of the project makes it easy to read - perhaps more images and the use of some tables might also assist in the presentation of this project.
--[[User:Z3288827|Leonard Tiong]] 10:49, 28 September 2011 (EST)

'''Group 6'''

*My first impression is that this project is lacking images. There is way too much text in comparison to images.
*An image would nicely complement the introduction
*I feel that history would work better in a timeline
*Epidemiology needs a table/graph
*Good links in signs/symptoms although another image would be nice
*Genetics needs to be explained a little better
*Student drawn images were great- obviously a lot of effort has been put into these
*Diagnostic test table needs an image and needs to be referenced properly
*Again, an image is needed for prognosis
*Glossary needs to be extended
*Overall a good project but you need to fix a few things

'''Group 6'''

*Introduction: the contend is ok, but the structure could be clearer

*History: too text heavy, a timeline would be nice

*Epidemiology: more content would be good

*Symptoms: the picture could be more general

*Genetics/ Aetiology: the structure could be better, maybe use some more subheadings, and put the gene profile in tables

*Pathophysiology: you need references

*Diagnostic tests: why does it say “insert images”, that should be fixed

*Treatment/ management: looks like there are some references missing? Deleate “Want to learn about more surgery and treatment methods?”, the contend is good, types of shunt would look better as a table

*Prognosis: references missing? good use of subheadings,

*Glossary: incomplete
--[[User:Z3387190|Z3387190]] 21:52, 27 September 2011 (EST)

'''Group 6 peer assessment'''
*Introduction is clear though lack images where a image of example of a blue baby would suffice
*History begins clearly though becomes about surgical history instead of the disease, where time line is not even present of how understanding of this disease improved.
*Epidemiology should be expanded either the genetics of the disease, in general have more information of the causes, incidence and distribution of the disease.
*Signs and symptoms poorly structured and requires more images also doesn’t have an introduction to the signs and symptoms. Although the extra links to comparison of the heart is useful and nicely used.
*Pathophysiology should add supplementary information to back up all the information.
*Diagnosis please add the images, while there is the content though no image following also first box has “insert text” very confusing.
*Treatment/management indicate the separation of surgery and other treatment types in the introduction which is lacking otherwise all is A ok
*Glossary needs to be referenced to other sections of the web page also expanded as most language used is unknown without a dictionary.
*Referencing needs to be fixed as links is not proper referencing also the repeats need to be removed
z3332250 23:53, 26 September 2011 (EST)

===Comments on Group Project 6===
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

--Z3389806 08:03, 26 September 2011 (EST)

'''Group 6 Critique'''

#• Introduction is ok, however it needs to be structured a lot better than what it is
#• History is interesting
#• Epidemiology needs a lot more detail. A few lines is not good enough
#• Signs and Symptoms is ok
#• Genetics needs to be explained a lot more clearly than what it is
#• Abnormalities is ok
#• Diagnostic tests table is impressive
#• Treatment/management section is very good
#• Prognosis and future directions section is great
#• Glossary is incomplete. Check the first term and fix this

--[[User:Z3289991|Robert Klein]] 19:05, 24 September 2011 (EST)

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

Group 6-
* No way near enough images. As I scrolled through there was HEAPS of text and only a few images, all of which are on the right hand side. It would be better if they were scattered around
* An image in the introduction would be helpful
* What are ‘tet spells’? mentioned in the introduction (described later but when seen in the introduction it looks like a typo)
* History would work better as a list of dates rather than paragraphs. I do like the section at the top with the quote though
* Epidemiology needs an image- perhaps a table or a graph.
* Signs and symptoms could do with another image to visualise the clinical manifestations
* I really liked the audio clips but the first one didn’t work on my computer? I couldn’t hear anything. Not sure if it was just me
* I think you can come up with a better way of formatting the genetics section. Maybe a table? The information is good it just looks a bit funny
* The pathogenesis doesn’t actually say HOW is happens in infants. Is this a condition formed during embryonic development or after?
* The diagnosis section is far from complete. This needs to be corrected
* Diagnosis section is also not referenced properly
* Why is there a reference at the bottom of the diagnosis section?
* As funny as this was: ‘Want to learn about more surgery and treatment methods? Check here!’…. maybe not appropriate sorry. It should be a little more formal. If you want the reader’s attention- try colour.
* Prognosis- image needed please. Maybe a graph?
* The glossary also needs to be extended
* The references need to be tidied up- there are also not many?
* You need to reference your images properly. ‘normal fetal blood flow and tetralogy of fallot’ is an example. You have but the copyright but not the reference. The web address is not a reference
* You are clearly on your way with the project but more work is required. You need to FINISH the content and format it a little better with more images.

''Group 6 Assessment'''
*First, I’d like to note good job on using a reference more than once in the correct way instead of referencing the same thing multiple times. At least this is done in the first few sections. First time I’ve seen this done correctly!
*The introduction, however, has no references whatsoever. Where did this information come from?
*It might also be good to add a simple picture in the introduction section so it looks more appealing.
*Good information included in the history section. It might look better if this were laid out in a bullet format though.
*The epidemiology section looks rather bland. Not only is there not a picture, but there also isn’t very much information included. Think about what else you could include here or what you could go into depth about.
*The signs and symptoms section has good information, but it might be a good idea to represent this information in a better format, possibly in a chart, with pictures of each symptom included in the chart.
*Finger-clubbing.jpg also needs a detailed description still.
*Good organization and format under the Genetics section.
*Under the pathyphysiology and Abnormalities section there are no references made. Where did this information come from? Diagnostic Tests and Treatment also needs more referencing.
*Pictures still haven’t been inserted into the Diagnostic Tests chart.
*More referencing is needed for the Prognosis section. Also, does the glossary terms need to be referenced?
*It would be a good idea also to 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. References 7-14 are the same reference. Fix these so they are under one single reference number.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Overall, there is a substantial amount of information given within this page, which is good. I like the basic format of everything and most of the pictures which are included. Just work on weaving everything together better and referencing things correctly. Good job!

--[[User:Z3391078|Z3391078]] 15:32, 27 September 2011 (EST)

'''Group 6'''
* Nice overall structure and good use of headings and subheading. It gives the page a nice flow.
* INtroduction is nice and straight to the point and gives the reader a good overview of your topic.
* I like the historical section with interesting subheadings used, maybe you could add a timeline just to simplify the info.
* Signs and symptoms nicely arranged. could you add some more pictures here?
* Pathophysiology and Abnormalities section need to have the references accompanying the information. Just so the read can identify where all the info is from.
* The diagnostic tests table would be nice with some colour and when the images are it will look complete. It's a little text heavy for a table maybe try bullet points. also the referencing system has changed in this table? and a little unsure of the reference at the bottom of the section?
* Treatment/Management section is nicely arranged.. could you add another picture here just to compensate for the amount of text. the table really brightens up the page!
* Future directions section is nicely summarised and I like the tone of voice used here. just make sure the referencing is correct as it is a little confusing and interrupts the flow of the section.
* Maybe the use of similar tables and colour scheme will increase the continuity of the page.
* Make sure your references are not doubled in the list.
* Ensure all of your pictures are correctly referenced.
* Make sure all acronyms and scientific wording is in the glossary.

*'''Intro''': What's a tet spell?
*'''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.
*'''Edidemiology''': Looks fine
*'''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.
*'''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).
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.
*'''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.
*'''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.
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.
*'''Glossary''': A bit poor. More technical terms need to be explained.
*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!

'''Peer Assessment: Group Project 6'''
*The introduction and the section on pathophysiology and abnormalities have no references. This needs to be rectified.
*The introduction and some of the history section have short paragraphs that are only one sentence long and would be improved, both for formatting and information purposes, by incorporating them into the rest of the information.
*Inserting a small timeline in the history section would make the sequence of events more accessible to the reader.
*Some sentences are too long such as, 'Children with TOF don’t grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth'. This sentence could be broken up and also improved by a greater explanation of why the process of growth is abnormal in TOF.
*Maybe explain more about what 'clubbing' is.
*In the diagnostic tests section the images need to be inserted and needs to be properly referenced. The information is good but as noted one section is totally void of text.
*The section on prognoses needs proper referencing.
*The section on future directions is well written, however the referencing needs to be adapted to the wiki format.
*Under the information in some of the images you have uploaded such as in the portait of A. Fallot, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The project is informative, however formatting and referencing are issues that need to be addressed.
--[[User:Z3217345|z3217345]] 22:23, 27 September 2011 (EST)

'''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.

--z3290815 20:31, 28 September 2011 (EST)

'''Peer Review'''

* really well done
* format and structure of the wikipage was consistent throughout

--[[User:Z3060621|z3060621]] 21:36, 28 September 2011 (EST)

Test:

{| style="color:black; background-color:#ffffcc;" width="85%" cellpadding="10%" cellpadding="15%" cellspacing="0" border="1"
| colspan="2" | '''Diagnosis'''
|}

--[[User:Z3291423|z3291423]] 11:57, 22 September 2011 (EST)

Hey Jaz, thanks for letting me know...my english can fail me at times.....lol...fixed it up... regards--[[User:Z3291317|Z3291317]] 18:49, 18 September 2011 (EST)

Hey guys! i just realised that the caption of helen taussig and ballot say portraight....not PORTRAIT!?!! i tried to change it but it don't really know how..anyone have any ideas to this?! :S thanks --[[User:Z3291423|z3291423]] 00:06, 17 September 2011 (EST)

Table Test! --[[User:Z3291423|z3291423]] 22:16, 16 September 2011 (EST)
{|
|-bgcolor="# 99FFFF"
| '''Type of Shunt'''
| '''Description'''
| '''Reasons for it not being used'''
| '''Image'''
|-
| Pott’s Shunt
| This shunt is a connection that is established between the lower part of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery.
| The shunt has a tendency to increase the pulmonary blood flow and it is also very hard to close when complete repair is undertaken
| Insert image
|-
| Waterston Shunt
| This shunt was placed between the back of the Aorta, to the right branch of the pulmonary.
| This shunt’s use is more suited to those with pulmonary artery stenosis and also the procedure is quite difficult to perform.
| Insert Image
|-
| Glenn Shunt
| The Super Vena Cava is anastomosed via a shunt to the right pulmonary artery.
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task.
| Insert image
|}

Table test (fingers crossed!) --[[User:Z3291324|Jacqueline Ellero]] 10:49, 15 September 2011 (EST)

==TOF diagnostic techniques==

{|border="1px" cellspacing="1" align="center" cellpadding="5" style="background:seashell"

|+ This table describes different diagnostic tests for TOF
! Diagnostic technique !! How the procedure works !! Presentation in TOF patient !! Image

|-
|Physical examination
|TOF is often diagnosed during fetal life by echocardiography (Apitz, Webb, & Redington, 2009). If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation. These signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with cyanosis and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. (Somerville, 1993)

|Insert text here
|Insert physical examination image
|-
|Heart murmurs
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh systolic ejection murmur may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). http://ccjm.org/content/77/11/821.full
|Insert heart murmur image
|-
|Electrocardiogram
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.(Somerville, 1993)
|Insert electrocardiogram image here
|-
|Chest radiograph
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnoses many conditions including the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. (Bailliard & Anderson, 2009) The radiograph will also show a right-sided aorta in approximately one-quarter of patients. (Somerville, 1993)
|Insert CXR image here
|-
|Echocardiogram
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. (Bailliard & Anderson, 2009)
|Insert echo image here
|-
|Magnetic resonance imaging
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect. (Somerville, 1993)
|Insert MRI image here
|-
|}

Hey peeps just put a intro just as a draft...tell me what you guys think of it. Edit it as you may wish.... And Jaq, if you describe briefly how each test works it would be good, regards --[[User:Z3291317|Z3291317]] 23:16, 14 September 2011 (EST)

hey jaz, ive fixed up the diagnosis, but feel free to add anything! or let me know if you think i should add anything. --[[User:Z3291324|z3291324]] 10:06, 14 September 2011 (EST) should i describe each diagnostic test!!??--[[User:Z3291324|z3291324]] 10:07, 14 September 2011 (EST)

Hey Guys! just added a very few changes, links etc to treatment. I've begun to add make a bit of notes on diagnosis that could just add a bit of detail to the diagnosis section. just wondered if any of you guys know what particular section of the ECG indicates...Left Ventricular Hypertrophy etc maybe ill call up a cardiologist :P nonetheless ill add references and some things to diagnosis tmrw night. regards, --[[User:Z3291423|z3291423]] 00:15, 14 September 2011 (EST)

Hey jaq. no particular order, the referencing system in the wiki automatically arranges it according to the order it is found in the text. In text referencing is NEEDED, lol. Type in the text title into Pubmed and when the article is found, the pmid code will be found at the bottom of the abstract for that article. if you cant figure out how to reference, put in the pubmed ids as intext citations then ill fix it for you...Make pathophys a bit more simpler, but do not compromise the anatomical words, i.e. write the anatomical word, then write in brackets what it means, eg. ''...anterolaterally (at the top away from the midline)'' is just an example (a crap one to lol). Also did you find any new info for diagnostic tests? and Rom, why did you remove info from the 22q section???? regards --[[User:Z3291317|Z3291317]] 22:02, 13 September 2011 (EST)

hey guys, quick question about the referencing. are they in any particular order? or should i just add mine to the end of the list? and do we need to do in-text referencing?? and how do you find the pmid code? also, any suggestions on how i should improve pathophys? ie make it more anatomical based or reword it so its simpler? thanks --[[User:Z3291324|z3291324]] 21:30, 13 September 2011 (EST)

Hey Rom, looking good thus far. if you need help with referencing even after trying so much i can help you during the 1 hour we have afta the lecture tomorrow to go through and help you fix em up... its a bit tricky but can get a handle of it... --[[User:Z3291317|Z3291317]] 20:37, 12 September 2011 (EST)

Hey guys sorry for the delay, but I'm slowly uploading all my stuff up. I'm just a bit confused about how I do the reference tag thing, as you can see there is a massive red thing on our reference list. I tried copying how you guys did it but I failed at it. I'll be posting some more in the next couple of hours, I just need to get a hang of this coding thing gah!
--[[User:Z3290841|z3290841]] 19:36, 12 September 2011 (EST)

hey rommel, we really need to see your part of the project and get your suggestions on parts we have done because its due on thursday --[[User:Z3291324|z3291324]] 19:16, 12 September 2011 (EST)

Hey Peeps, Just reconstucted the referencing so they are done exactly as it should be... Also just uploaded a pic of Mr fallot Himself without any copyright restrictions ( aha ow ye ow ye, took me long before i found it lol). I left the intext references jac and jaz put in their sections for future reference. Thats about it for now... Jaz i hope u liked the pics i showed you, and i hope rom is going well in his section... See yous soon... Regards --[[User:Z3291317|Z3291317]] 17:36, 11 September 2011 (EST)

update: uploaded the drawn images, took ages but its finally done :) and I've just finished the future directions :) so it should be fine to edit and look over in the next couple of days!
regards --[[User:Z3291423|z3291423]] 13:16, 11 September 2011 (EST)

looking good jaz. thanks for the articles fru. ive had a quick look at them but will need to fix it up after work this arvo! --[[User:Z3291324|z3291324]] 11:59, 11 September 2011 (EST)

Hey Jac, ive got 2 articles that i will send to your email, both talk about Cardiac Magnetic Resonance, one some detail about electrocardiography. Also, Jaz i have an article that has a section based on 'Future Innovations' for TOF, have a read and i reckon it will help out with the future directions part... i will send these articles to your emails so look at them when yous can... and rom, you breathing my friend?... regards --[[User:Z3291317|Z3291317]] 01:29, 11 September 2011 (EST)

hey guys, just reworded diagnosis so it makes sense. can anyone suggest any good articles to read for diagnosis? im having trouble accessing a lot of articles (they keep asking for passwords) and a lot of the articles dont discuss diagnosis in much detail at all. help is much appreciated!! thanks :) --[[User:Z3291324|z3291324]] 21:12, 10 September 2011 (EST)

hey rom, this might be helpful for genetics. not sure what youve got already though http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747103/
--[[User:Z3291324|z3291324]] 20:50, 10 September 2011 (EST)

also what should i do about the symptoms-pathophys overlap. should i alter the pathophys so its more anatomical like in the below article??--[[User:Z3291324|z3291324]] 20:10, 10 September 2011 (EST)

On to it now fru. thanks for the article. should i reword pathophys too so its easier to read/understand?--[[User:Z3291324|z3291324]] 20:08, 10 September 2011 (EST)

Hey Fru: in regards to the below comments, im working on future directions now :) also i read through the history section and it seems a lot more better :) just one mistake is the
"durng such operations there need". Ill have my edited prognosis and futures up by tonight! :) ohh and the heart! regards --[[User:Z3291423|z3291423]] 11:03, 10 September 2011 (EST)

Hey Jac i was reading the article: Review - Tetralogy of Fallot by Frederique Bailliard and Robert H Anderson ( im sure you have this one) and theres a section absed on " Anatomical variants of Tetralogy of Fallot, and associated anomalies". i believe if you could also include this section into the Pathophysiology section it would be great! Furthermore would you please do the things Mark said in regards to your sections it would be good, especially the diagnostic tests part :). Also to everyone we need to get Future Directions and especially Genetics up ASAP! thus respective people have them completed asap. --[[User:Z3291317|Z3291317]] 22:49, 9 September 2011 (EST)

Hey jaz, the prognosis sounds pretty good. maybe expand/explain how the hypoxic spells, brain abscesses etc cause death. i think in general we could expand upon most sections. off to work now guys but ill fix up my couple of sections tonight/tomorrow morn! --[[User:Z3291324|z3291324]] 08:30, 9 September 2011 (EST)

Thanks Fru! I will definitely crack onto those suggestions, I'm going to first email the owner of the children's hospital video on youtube to get permission for using the video, and then ill put it up in my section.
ALSO, I've nearly done the picture! I've got an outline and as your reading this, i should have it coloured, labelled and ready for upload! :D

have a great weekend guys!

Reagards
--[[User:Z3291423|z3291423]] 23:29, 8 September 2011 (EST)

Hey jaz just read your prognosis section. You made it well, however,i picked up 2 things you could do and it woould be good if you do them: 1. The causes of death after no surgery has done; if you can explain how these 'causes of death' occur due to TOF, it will portray the role TOF has in these problems. 2. You should talk about any complications that could arise in both patients that dont have corrected TOF and the ones who do have the surgery (i.e. any conditions that could develop after having the surgery or not, not just the death of the patient if they dont correct their heart). Other than that great work! :) --[[User:Z3291317|Z3291317]] 23:17, 8 September 2011 (EST)

Ye Jaz, thanks for the pic. Aswell ive attached a reviewed file of the treatment section on an email i sent to you. Maybe the youtube cideo based on the TOF fix up can now be put under this section as an embedded video... --[[User:Z3291317|Z3291317]] 22:19, 8 September 2011 (EST)

hey jaz, the treatment section is much better, much easier to read. thanks for the heart pic! im pretty sure my section is he one that is too "verbose" so anyone feel free to fix it up--[[User:Z3291324|z3291324]] 19:47, 8 September 2011 (EST)

Hey Guys! sorry prognosis took me a bit longer to do, but It will be up by tonight :) and ill upload the heart pic as well :) which took forever to make!
regards --[[User:Z3291423|z3291423]] 16:05, 8 September 2011 (EST)

hey guys just put up some diagnosis, let me know if you want me to add anything to it. furkan, glossary looks good! rommel, how are you going with the genetics do you need any help? and jaz are you able to post up the prognosis? once they are all up we should go through and edit them all together and fix up the wording. --[[User:Z3291324|z3291324]] 15:50, 8 September 2011 (EST)

Hey peoples...im going to start constucting the glossary wordbank as i read the entire document. Please add words yous think i missed out on... Also i found a pic of Mr Fallot but i think theres copyright rights on it. i think i gotta clear it somehow...--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

hey jaz, i think the treamtment section is alright. maybe reword the first bit into sentences (i think it was the bit on how severe the cyanosis is) so its a bit clearer. but otherwise good :) what do you think about pathophys?--[[User:Z3291324|z3291324]] 12:40, 7 September 2011 (EST)

hey guys, i cant tell if this pic has copyright or not. can someone please have a look for me? http://www.nhlbi.nih.gov/health/health-topics/topics/tof/ thanks!--[[User:Z3291324|z3291324]] 09:49, 6 September 2011 (EST)
--> REPLY: I looked at the pic and looks great. however, i couldnt see if it was copyright or not. HOWEVER, it is found on a public government website, and from what i remember Mark said we can use these materials. To make sure just please check it with him aswell. Also, im going to format your pathophysioligy section now so it looks prettier :)--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey guys, i Just finished the Treatment part, I've got palliative in this heading to still complete but Its very brief so i thought id get cracking on getting that drawing done and also the prognosis will be up by tomorrow! also check this out! http://www.nemours.org/content/dam/nemours/www/filebox/service/medical/cardiology/defect/tof.swf
--[[User:Z3291423|z3291423]] 23:57, 5 September 2011 (EST)
-->REPLY: Cool animation. Would we use an external link to this animation due to copyright restrictions?--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey Peepz

I just finished the sections of History, Signs and symptoms and Epidemiology

just please check these sections, especially the epidemiology one, do yous want it more detailed or is it enough?

z3291324 your section seems alright so far, show us your edited version so we can fully critic it then.

p.s. the post below my one i dont really understand itl who is speking to who and what are yous refering to? lol

Regards --[[User:Z3291317|Z3291317]] 23:44, 4 September 2011 (EST)

j: the article on future treatment directions sounds good. i might add some of the info in to the pathophysiology section because it links in well with the pulmonary stenosis and right ventricular hypertrophy. --[[User:Z3291324|z3291324]] 13:47, 2 September 2011 (EST)
I think this article makes some good points which could be added into the treatment section (eg discuss treatment/surgery after birth and also follow up treatments in adulthood- pulmonary valve replacement etc due to valvular incompetence and regurgitation because of the growing heart)

=pathophysiology=
hey guys. ive written some basic notes (UNEDITED) for pathophysiology. Just want to get an idea of how much detail i should go into before i start adding links to journal articles etc. can someone please have a quick look through and give me an idea of how much more detail is needed. thanks :)

The four features of tetralogy of fallot are pulmonary stenosis, overriding aorta, ventricular spetal defect and right ventricular hypertrophy. These features result from the anterosuperior displacement of the infundibular septum. The severity of symtpoms is determined by the extent of right ventricular outflow obstruction. 
'''Pulmonary stenosis'''
(Symptoms include cyanosis, right ventricular hypertrophy, hepatomegaly and peripheral oedema (of the legs). More mild symptoms include sudden fainting and dizziness from exercise. ) 
Valvular or infundibular stenosis (narrowing of the outflow tract of the right ventricle). Obstructs the outflow of blood from the right ventricle reducing pulmonary flow. If the pulmonary stenosis is mild, a left to right shunt (with no cyanosis) will form, due to the higher pressure in the left ventricle. However, significant pulmonary stenosis can raise right ventricular pressure above the left ventricular pressure and cause a right to left shunt (cyanosis etc). The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. 
'''Overriding aorta'''
The aortic valve has a biventricular connection. Instead of being positioned over the left ventricle, the aortic valve is located above the interventricular spetal defect allowing blood from both the right and left ventricles to pass through the aortic valve. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. Because the right ventricle receieves deoxygenated blood from the systemic circulation, the percent oxygenation of bloood entering the aorta and hence back into the systemic circulation is decreased. 
'''Ventricular septal defect'''
The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. During ventricular contraction, blood from the left ventricle passes into the right ventricle and then re-enters the pulmonary circulation. Leakage of blood from the left to right ventricle raises the right ventricular volume and pressure resulting in pulmonary hypertension. (Shortness of breath, dizziness and fainting) If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience cyanosis and deoxygenated blood is by-passing the lungs and entring the systemic circulation. (also breathlessness, poor feeding and failure to thrive in infancy.) 
'''Rigth ventricular hypertrophy'''
Compensatory response to pulmonary stenosis ...to be contined.

--[[User:Z3291324|z3291324]] 13:38, 2 September 2011 (EST)

=link to pathology textbook=

hey guys, this is the link to tetralogy of fallot in robbins pathology
--[[User:Z3291324|z3291324]] 13:05, 2 September 2011 (EST)

=More genetics and Surgery=

Hey Peeps, i forund another article in regards to Genetics as it does an genotype-phenotype anaylis os TOF Patients. Have a read and see if it can help in the assignment subsection. if you cant get the full article tell me and ill give you the pdf of it.

Article: PMID: 19948535

And Regards to surgery and its prognosis post-operation i found these articles that may be helpful for 3291423. Again if yous cant find the pdf tell me and i'll send yous the pdf articles of these.

Articles: PMID: 20091166 ; PMID: 21769263 ; PMID: 21566339 (hey 3291423 this is the article i showed you in the lab and you wanted it from me)

Anyways peeps i hope all the assignments are coming along well

Regards --[[User:Z3291317|Z3291317]] 19:03, 1 September 2011 (EST)

REPLY: Thanks z3291317, I had a look through the files and am using them now for summarising :) also, can you send through the picture of what you want the abnormal TOF heart to look like and ill get cracking on it to produce/draw it :)

regards --[[User:Z3291423|z3291423]] 22:15, 1 September 2011 (EST)

=Genetics=
Hey guys, found some articles relating to genetics and the deletion of the 22q11 gene. take a look :)
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

AS Bassett, EWC Chow and J Husted et al., Clinical features of 78 adults with 22q11 deletion syndrome, Am J Med Genet 138 (2005), pp. 307–313. http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science?_ob=MiamiImageURL&_imagekey=B6T18-3V8RDDJ-11-1&_cdi=4884&_user=37161&_pii=S0735109798002599&_check=y&_origin=&_coverDate=08%2F31%2F1998&view=c&wchp=dGLbVlW-zSkWz&md5=0a4f32c3b75ebff2513309081ac0468f&ie=/sdarticle.pdf

http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

=Treatment and future directions info/readings=

Hey guys, found this really amazing article about treatments and their repercussions http://www.ccjm.org/content/77/11/821.long#abstract-3
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

=Online lab 4 info=
I my friends , colleagues and countrymen am going to be undertaking the research of the subsection Genetics/Aetiology in the topics that have been discussed. --[[User:Z3290841|z3290841]] 10:18, 25 August 2011 (EST)

Im going to be researching Treatment/Management, Prognosis & Future directions. - z3291423

regards, --[[User:Z3291423|z3291423]] 23:30, 24 August 2011 (EST)

Thanks for typing them up. I'm going to research Pathophysiology and abnormalities and diagnostic tests.
--[[User:Z3291324|z3291324]] 15:40, 24 August 2011 (EST)

Hey Group 6

From the Meeting on Tuesday after the Embryo lecture, we had concluded that we are going to divide the group project of TOF into the following sub-sections (if i am not mistaken):

* Introduction
* History
* Epidemiology
* Signs and Symptoms
* Genetics/Aetiology
* Pathopgysiology and Abnormalities
* Diagnostic Tests
* Treatment/Management
* Prognosis
* Future Directions
* Glossary
* References

From these subsections, I (z3291317) will research the History, Epidemiology and Signs & Symptoms subsections of the group Project.

Just wanted to put forward my part for the group project :)

Regards --[[User:Z3291317|Z3291317]] 15:01, 24 August 2011 (EST)

=Resources=
Hey Group 6

When i was looking around for info in regards to TOF, i found some videos on youtube made by an american hospital which we could use on our page in the "more info" section. Check them out and tell me what yous think...

- http://www.youtube.com/watch?v=ACRfFkxow7w
- http://www.youtube.com/watch?v=jgLC2QABcxo

So what you guys think? --[[User:Z3291317|Z3291317]] 22:54, 21 August 2011 (EST)

COMMENT: great stuff! that really is a great tool, maybe we can incorporate that in as a link, or something to really explain it! without all the mumbo jumbo :) --[[User:Z3291423|z3291423]] 22:22, 22 August 2011 (EST)

=Articles=

Found really good article detailing some clinical aspects http://journals.cambridge.org.wwwproxy0.library.unsw.edu.au/action/displayAbstract?fromPage=online&aid=331031 its called: The clinical anatomy of tetralogy of Fallot, http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0140673609606577 - Tetraology of ballot by christian apitz, just google scholar it via unsw or use the link I've given you :) --[[User:Z3291423|z3291423]] 19:10, 20 August 2011 (EST)

=Images=
Hey guys, this is an image of tetralogy of fallot with pulmonary atresia

[[File: Tetralogy of Fallot with pulmonary atresia.jpg]]
--[[User:Z3291324|z3291324]] 22:07, 17 August 2011 (EST)

Hey guys, just found this still frame showing large ventricular septal defect, aortic override, and right ventricular hypertrophy which are all very common to patients with ToF
[[File:Some common effects for patients with Tetralogy of Fallot.jpg]]
--[[User:Z3291423|z3291423]] 21:43, 17 August 2011 (EST)

Hey guys this is my image of our disease, it is just outlining some of the basic changes that happens to the heart, mainly the right ventricle.

[[File:Right ventricle of heart with Tetralogy of Fallot.jpg]]

--[[User:Z3290841|z3290841]] 13:42, 17 August 2011 (EST)

----

Hey Group 6, its z3291317

I just wanted to make it clear that we add all new entries into our discussion page at the top of the page and not at the bottom of it. Thats how we are told to edit this discussion page.

Anyways this is my Image for Lab 3 Question 2:

[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg]]

I hope it would be beneficial for our page...

--[[User:Z3291317|Z3291317]] 12:05, 17 August 2011 (EST)

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)
Hey Group 6

i just done some research on a possible group project subject. It is quite detailed and interesting (to me) disease to write on.What do you guys think? Here is the review and research article for it:

The Disease:'''Tetralogy of Fallot'''

Review Article:

Orphanet J Rare Dis. 2009 Jan 13;4:2.

'''''Tetralogy of Fallot.'''''

Bailliard F, Anderson RH.

North Carolina Children's Heart Center, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. frederique_bailliard@med.unc.edu

Link: <ref><pubmed>19144126</pubmed></ref>

Description: This paper gives an overview about the disease, how it happens, and clinical manifestations.

Research Article:

J Med Genet. 2010 May;47(5):321-31. Epub 2009 Nov 30.

'''''Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.'''''

Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U, Hoyer J, Kaulitz R, Singer H, Rauch A.

Institute of Medical Genetics, Schorenstrasse 16, CH-8603 Zurich-Schwerzenbach, Switzerland. anita.rauch@medgen.uzh.ch

Link: <ref><pubmed>19948535</pubmed></ref>

Description: A study was done to see the prevalent phenotype for Tetralogy of fallot, and it was found that the 22q11.2 deletion was the most common type in Tetralogy of Fallot.

'''''References:'''''

<references/>

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)

----

--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

Hey Guys,

I did research on Cystic fibrosis and these are the 2 articles that I found that explains a lot about the disease, and the genetic research on it.

Review Article:

'''Cystic Fibrosis: Seminar'''

Description: This is basically outlining the pathophysiology of the disease, disease manifestation,current treatments diagnostic tool.

Ratjen F & Doring G.(2003).Cystic Fibrosis: Seminar.''The Lancet'', 361, 681-9. Retrieved from http://www.sciencedirect.com/science/article/pii/S0140673603125676

Research Article:

'''Gene expression profile study in CFTR mutated bronchial cell lines'''

Description: This article provides information about the severity of gene expression in relation of the extent or type of mutation.

Gambardella S, Biancolella M, D'Apice M, Amati F, Sangiuolo F, Farcomenti A, Chillemi G, Bueno S, Desideri A & Novelli G.(2006).Gene expression profile study in CFTR mutated bronchial cell lines.''Clinical and Experimental Medicine '', 6, 157-65. Retrieved from http://proquest.umi.com/pqdlink?Ver=1&Exp=08-05-2016&FMT=7&DID=1187181501&RQT=309&cfc=1

--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

--[[User:Z3291324|z3291324]] 20:48, 10 August 2011 (EST)

Hey guys, I like the disease that Furkan found (tetralogy of fallot)! What does everyone think?

These are the two articles I found. The review article gives a pretty good description of the disease, symptoms, treatment and complications etc. The research article looks at some of the genetic causes.

Goldmuntz, E., Geiger, E., & Benson, D. W. (2001). NKX2.5 mutations in patients with tetralogy of fallot. Circulation, 104(21), 2565-2568.

Apitz, C., Webb, G. D., & Redington, A. N. (2009). Tetralogy of Fallot. Lancet, 374(9699), 1462-1471.

Hey kiddes just done some research! check it out, its about Hypoplastic left heart syndrome

Review article:

2001 May-Jun;21(3):705-17.
'''Hypoplastic left heart syndrome.'''
Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP.

Link: [http://www.ncbi.nlm.nih.gov/pubmed/11353117]

Research:

2011 Aug 1;108(3):421-7. Epub 2011 May 31.
'''Prenatal diagnosis of hypoplastic left heart syndrome in current era.'''
Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ.
Link: [http://www.ncbi.nlm.nih.gov/pubmed/21624547]

References
<references/>
1. Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP ""Hypoplastic left heart syndrome.""Radiographics. 2001 May-Jun;21(3):705-17 <ref><pubmed>11353117</pubmed></ref>

2. Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ ""Prenatal diagnosis of hypoplastic left heart syndrome in current era."" Am J Cardiol. 2011 Aug 1;108(3):421-7. Epub 2011 May 31 <ref><pubmed>21624547</pubmed></ref>

==Peer Assessments==
* I would suggest placing the history section into a timeline or table format just so that significant dates are more clear and emphasised.
* The gene profile section was great. It was in detail, it was coherent and the inclusion of gene images enhanced my understanding of this particular section.
* Maybe for the “how the procedure works” section of the diagnostics table could have been summarised into a flow diagram or through images, rather than having a chunk of text. This could make it more straight forward to the reader.
* Your website was generally well-written and to the point. You varied your formatting regularly which made your page entertaining.
* My last suggestion would to only use the image of the shunt once and finding a different image as the repetitiveness of this is slightly disengaging
--[[User:Z3332629|z3332629]] 15:26, 22 September 2011 (EST)