Fragile X syndrome is the most common monogenic inherited cause of intellectual disability. In contrast to other diseases with X-linked recessive inheritance, fragile X syndrome shows healthy male carriers, and in some of the female patients, symptoms are as severe as in males. The incidence of affected males is estimated to be 1:5164 according to a 2009 study.
The cause of fragile X syndrome is a CGG triplet repeat expansion in the non-translated 5′ region of the FMR1 gene on the long arm of the X chromosome. The most frequent normal alleles in the general population have a length of 29-30 CGG repeats. Alleles in the range of 45 to 54 repeats are defined as gray zone alleles (EMQN ring trials). Some instability is already present at this repeat count, regardless of the sex of the carrier; however, expansion to a full mutation in one generation has not yet been observed in this range.
Alleles with 55 to 200 CGG repeats are referred to as premutation. In females, inheritance of premutations is unstable, usually leading to an extension of more than 200 triplets (full mutation) when they are passed on to the next generation. Above this length, methylation of cytosine residues of the repeat and adjacent regulatory elements occurs, ultimately leading to inhibition of transcription and consequent failure of the FMR1 gene product. In males, the premutation is stable when passed on to the next generation. Mothers of children with a full mutation are obligate carriers with either a premutation or a full mutation. The risk of recurrence is up to 50% for affected children depending on the sex or the length of the premutation in the mother.
In the presence of the full mutation, the developmental delay is first noticeable in childhood and usually affects speech more than motor skills. The children often have slightly abnormal measurements for body length and head circumference. Occasionally, symptoms of connective tissue weakness such as hyperextensible joints and muscle hypotonia are present. Hyperactivity and autistic behaviors are characteristic features. Apart from rather large ears, other phenotype features, such as an elongated face and prominent chin, are not very pronounced in childhood but characterize adults with fragile X syndrome. Postpubertal macroorchidism is often seen in males. Female carriers of the full mutation can show variable symptoms ranging from an inconspicuous phenotype (about 30%) to intellectual disability of a severity similar to that seen in males. About 20% of premutation carriers have premature menopause (fragile X asociated pimary ovarian insufficiency, FXPOI). In older premutation carriers, particularly males, more than 30% show a progressive neurological disease pattern consisting of intention tremor, gait ataxia, parkinsonism, autonomic dysfunction and dementia, which is called fragile X tremor/ataxia syndrome (FXTAS).
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