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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