2011 Group Project 5

From Embryology
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

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Introduction to Fragile X Syndrome

Fragile X Syndrome does not create X-Men. Sad face.

History of the disease

Name origin

Fragile X Syndrome is given its name due to an abnormality of the X chromosome. The abnormality arises from a site of constriction on the long arm of the chromosome X which is prone to breaking, resulting in a chromosomal lesion[1]. The rare fragile site on the X chromosome is known as FRAXA and and the gene sequence CGG is repeated within the untranslated region (UTR) of the FMR1 gene that is affected [2].

Martin and Bell (1943)

It was well known in the late 19th century that there were an excess number of retarded males in comparison with retarded females. It was Martin and Bell in 1943 who first reported that the reason for the excess number of retarded males was due to a sex linked inheritance associated with severe mental retardation. 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 not associated with microcephaly or microphthalmia [1].

Lubs (1969)

The first documented report of the existence of the marker X chromosome was by Herbert Lubs. After studying a family of three generations which included four retarded males, it was evident that all four males possessed the marker X chromosome as well as the heterozygous females who were not considered clinically retarded [1].


Full mutation in Caucasian male populations (European descent)

The combination of point estimates for eight studies suggests that the prevalence of Fragile X Syndrome ranges from 1 in 3,717 to 1 in 8,918 males in the general population[2].

Full mutation in other male populations

There are an inadequate number of studies conducted on Fragile X Syndrome in other populations. However, those studies that have been done, suggests that there is a difference in prevalence across populations; [2]

  • One study proposed that the prevalence of the fragile X syndrome 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 fragile X syndrome of pure Basque origin in a mentally retarded population and a lower frequency of large CGG repeats.
  • Investigators in Nova Scotia reported an absence of fragile X cases among their mentally retarded population.
  • The prevalence in African-derived populations is approximately 1 in 2,500 in the general population, which is higher than that observed in Caucasian populations.

Full mutation in the female population

Not a great lot is known amongst the female population. The expected prevalence among females affected with the fragile X syndrome is approximately 1 in 8,000 to 1 in 9,000 in the general population. This is based on the fact that the prevalence in Caucasian males is around 1 in 4,000 and only females can transmit full mutations to their offspring[2].

Premutation in males

(Premutation = 61–200 repeats of the gene sequence CGG)

The prevalence of premutations in males is approximately 1 in 1,000 in the general Caucasian population[2].

Premutation in females

The prevalence of premutation carriers is high, with point estimates ranging from 1 in 246 to 1 in 468 in the Caucasian general population[2].

Screening/Population testing


Genetic Contribution

Involving changes to 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 FMR1 gene on a fragile segment of Xq27.3, the disease commonly occurs in people without a family history.

In Fragile X Syndrome, a CGG triplet repeat on a fragile segment of Xq27.3 is amplified and can take 4 forms, each of whose increasing amplification correlates with varying degrees of the disease: common, intermediate, premutation and full mutation[3].

  • Common amplification typically presents with anywhere between 6 and 40 repeats; 30 repeats is most common[4]. 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[5][6][7].
  • 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 this regulatory segment silences the gene, Elongation to this degree results in methylation of the CpG island which typically regulates expression of the FMR1 gene. Loss of the gene causes fragile X mental retardation protein 1 to be under-expressed, interfering with nervous system functioning[8]. The prominence of FMR1 mRNA in the normal developing foetal central and peripheral nervous systems means that its absence brings about the mental retardation typical of sufferers of the disease[9].

Development of the Disease

Fetal Development

At Birth

In Adult

Signs and Symptoms

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.

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.

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.

Recent Research

Autism and Fragile X Syndrome




  1. 1.0 1.1 1.2 <pubmed>6348096</pubmed>
  2. 2.0 2.1 2.2 2.3 2.4 2.5 <pubmed>11545690</pubmed>
  3. <pubmed>11545690</pubmed>
  4. http://www.fragilex.org/html/premutation.htm
  5. <pubmed>10208170</pubmed>
  6. <pubmed>11445641</pubmed>
  7. <pubmed>12638084</pubmed>
  8. http://ghr.nlm.nih.gov/condition/fragile-x-syndrome
  9. <pubmed>8348153</pubmed>


CGG: Is a genetic code which is a set of rules by which information encoded in genetic material (DNA or mRNA sequences) is translated into proteins; in this case the protein is Arginine

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.

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