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Fragile X syndrome
- Genetics of mental retardation

Fragile X syndrome is the most common inherited cause of mental retardation and originally derived its name from the characteristic nonstaining band or fragile site on the X-chromosome. It affects approximately 1 in 4425 to 6045 males and causes mental retardation in 1 in 8000 females. This syndrome accounts for half of all the X-linked mental retardation cases and around 0.6% of the population who show mental retardation. The mean IQ scores in Fragile X males seems to decline with increasing age, a phenomenon also described in people with Down syndrome.[11] A curvilinear relationship exists between the length of CGG repeat (the mutation) and the level of intelligence in Fragile X adults.[12]

In normal individuals between 6 and 54 CGG repeats are expected with an average of 30 repeats. The mutation for Fragile X is a heritable unstable sequence of trinucleotide CGG repeats ranging from 230 to over 1000.[13],[14] The full mutation, when the repeat sequence reaches a critical length of about 200 copies, is associated with hypermethylation of the repeat and adjacent region. This results in the failure of FMR1 transcription and an absence of the FMR1 gene protein product (FMRP), which is responsible for the characteristic clinical features of fragile X syndrome.[15] 'Anticipation' occurs when premutations often expand to full mutations while transmitted by female carriers and the clinical severity of the disease increases with each successive generation. A milder form of mental retardation expressed as FRAXE occurs by FMR-2 mutation.[16]

The key clinical characteristics of fragile X syndrome are mental retardation, large ears and a long face and macro-orchidism. In some adults, there is a characteristic facial appearance, with a large forehead with supra orbital fullness, long face, long nose, prominent jaws, high-arched palate and large ears with a bat-eared appearance. Eye abnormalities such as pale irises may be a subtle finding in some cases.[17] Epilepsy is reported in about 25% of the cases.

Many affected individuals show higher rates of speech and language problems, attentional difficulties and hyperactivity and autistic-like features such as gaze avoidance and hand flapping.[18],[19] The observation of this type of behavioural phenotype in conjunction with early reports of increased rates of Fragile X in autism led to interest in the relationship between Fragile X and autism.

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