2011 Group Project 5

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Note - This page is an undergraduate science embryology student group project 2011.
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip


2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

Fragile X Syndrome

--Mark Hill 15:06, 8 September 2011 (EST) This is a reasonable start, you have identified most key topic issues. The formatting of your subheadings is all wrong. There is currently not a single figure, illustration or table in this project. There should at least be something showing the gene, location and genetic mutation.

<wiki>=Fragile X Syndrome = </wiki>

then

<wiki>==Introduction == </wiki>

and so on through all sub-headings, with appropriate sub-sub headings or bullet/numbered lists.

  • Introduction - should be just that and be before history of the disease section. Fix this.
  • History of the disease - just history will be fine. The writing is not very clear you need to go through this and restructure, perhaps by someone else not the original author who may not see the problems. Really, only 3 parts to the history of this disease, you have not done your research.
  • Epidemiology - The first part of this text looks to have come directly from (http://www.cdc.gov/genomics/resources/books/HuGE/chap23.htm), not good enough. The (CGG) expansion has not even been explained.
  • Etiology - Reasonable description, but this section could be illustrated with what you are trying to describe.
  • Development of the Disease - Fetal not Foetal please. "evincing" remember your audience is university level student. Hoeft et al. (2010), place the citation directly after date. Postpubescent, where is the reference for what you are stating here.
  • Signs and Symptoms - OK here, not the best, but better than other parts of the project so far.
  • Recent Research - Rapin & Tuchman, (2008), place the citation directly after date. Diagnosis and Treatment, should this not have been in another section? Does not sound like recent research. This whole section needs some structural work.

Introduction

History of the disease

Name origin: Due to the expansion of the nucleotide triplet, the extremity of the long arm of chromosome X appears elongated[1] creating a site of constriction which becomes fragile and is prone to breaking[2].

Thomas Hunt Morgan (1910): Demonstrates that when a gene is located on the X chromosome of the fruit fly, the characteristic appears more frequently in males than in females[3].

Martin and Bell (1943): 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 [2].

Lubs (1969): The first documented report of the existence of the marker X chromosome was by Herbert Lubs[2]. Lubs developed the chromosomal test for Fragile X however it was not used extensively until the late 1970's[4].

Sutherland (1977): Showed Lubs findings to be a reliable through cells cultured in a folate deficient medium. [5].

Turner and colleagues (1980): 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[6].

Verkerk (1991): Discovered and described the FMR1 gene and encouraged the medical and psychopedagogic research of Fragile X Syndrome[1].

Hagerman and colleagues (2001): First recognized Fragile X-associated tremor/ataxia syndrome (FXTAS)[7].

Paul and colleagues (2010): 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. [8].

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[9].

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[9]. 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 allele [9].

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. For example:[10]

  • One study proposed that the prevalence of FXS is higher amongst Tunisian Jews compared with Caucasians by as much as 10 times more.
  • Another study established a lack of large CGG repeats in Native American populations to suggest a lower prevalence of the syndrome amongst this population.
  • 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.


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[11].

Population screening for Fragile X Syndrome has been largely debated[11].

Arguments supporting the use of population testing include:[11]

  • 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:[11]

  • 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[12]
    • FXPOI: Fragile X-associated primary ovarian insufficiency.Approximately 25% of female premutation carriers have fragile X-associated primary ovarian insufficiency[12]
    • 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

Etiology

Genetic Contribution

Involving 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[10].

  • Common amplification typically presents with anywhere between 6 and 40 repeats; 30 repeats is most common[13]. This form presents with no signs or 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[14][15][16].
  • 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 expression, the loss of which inhibits the binding of transcription factors, effectively silencing the gene and causing fragile X mental retardation protein 1 (FMRP) to be under-expressed. Transcription is similarly inhibited by methylation-induced chromatin condensation[17]. Repression of FMRP expression interferes with nervous system functioning[18]. Studies have also suggested FMRP playing a role in synapse formation and function[19][20], being significantly expressed in the brain and testes[21]. 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[22]. 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[23][24]. Its role in RNA metabolism sees FMRP repressing translation of mRNA at synapses via interaction with proteins required for miRNA function[25].


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[26].

Development of the Disease

Developmentally, mental retardation is the most common evidence of Fragile X Syndrome, with patients typically evincing IQs of 20-70[27][28]. 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 macrocephaly is expressed: ears, the mandible and the forehead are prominent. Given the hypothesized role of FMRP in proper neuronal development[29] and the role of neural crest migration in fetal facial skeleton development[30], 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[31][32]. 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[33]. Coincidentally, enlargement of the caudate nucleus and 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[34].

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[35][36]. Joint hyperflexibility, protruding ears and the macroorchidism evident after puberty are examples of deformities related to connective tissue dysplasia[37], 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[38], 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[39] during puberty mean that in post-pubescent male patients, macroorchidism is evident. Increased proliferation of Sertoli cells has been noted in these cases[40] 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[41].

Signs and Symptoms

Fragile X syndrom 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 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 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 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, stereotypies (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. 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. 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.

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). 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. 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 asympotomatic carrier males) suggests that carrier males have greater neuropathology with larger expansions in FMR1 mRNA transcripts.

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.

Diagnosis

Modern-day approaches to diagnosing FXS involve the use of immunocytochemical and molecular techniques. [42] Such techniques include:

  • Southern Blot is the most popular procedure in most laboratories as it allows for the detection of mutations and determination of methylation status in the one test. [42]
  • Modified PCR techniques, such as PCR that is methylation specific, are also an option but they are not yet as popular as other techniques for diagnosing FXS as they possess difficulty amplifying CGG repeats, interpret results in female patients and differentiate between mosaic patterns. [42]
  • Another option for diagnosing FXS is by utilizing the FMRP antibody test. This test is suitable for the screening of large populations of FXS patients who have no CGG expansion. This test is still, however, not widely used. [42]

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. [42]

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.

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.” [43]


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.” [43]


Treatment of Seizures: 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. [43]


mGluR5 (metabotropic glutamate receptor 5 pathway) Antagonists: 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. [43]


Behavioural Interventions: Studies have shown that environmental variations impact on behaviour. For instance, fewer autistic behaviours as we ll 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. [43]


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. [43]


Recent 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) have characterized autism into three key manifestations:

  1. Poor communication skills, impaired sociability and difficulty in developing relationships.
  2. Perseveration, rigidity and resistance to change.
  3. Impairment in language, difficulty in using abstract concepts and delayed symbolic play. [44]

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. [45]


In their study on the link between FXS and autism, Hagerman et al., (2010) 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 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.” PMID 20858229


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. PMID 20858229

Glossary

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.

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).

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.

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.

Macroorchidism: Abnormally large testes.

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

References

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2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip