Fragile X syndrome is the most common monogenic inherited cause of mental retardation. In contrast to other diseases with X-linked recessive inheritance, Fragile X syndrome shows features like healthy male carriers and female patients presenting partially similar severe symptomatology as 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 (fragile X-mental retardation) 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 EQA). At this repeat count, regardless of the sex of the carrier, some instability is already present, but no expansion to a full mutation in one generation has yet been observed in this range.
Alleles with 55 to 200 CGG repeats are referred to as premutation. In females, premutations are unstably inherited, 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 stably passed on to the next generation. Mothers of children with full mutation are obligate carriers with either a premutation or already 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, usually affecting 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 observed as characteristic features. Apart from rather large auricles, other phenotype features such as elongated face and accentuated chin are still not very pronounced in childhood, but characterize adults with fragile X syndrome. Postpubertal macroarchy is often seen in males. Female carriers of the full mutation can show a very variable symptomatology ranging from an inconspicuous phenotype (about 30%) to a similarly severe mental retardation as in males. About 20% of premutation carriers have premature menopause (FXPOI). In older, mainly males, more than 30% of the premutation carriers show a progressive neurological clinical picture consisting of intention tremor, gait ataxia, parkinsonism, autonomic dysfunction and dementia, which is now called “fragile X tremor ataxia syndrome” (FXTAS).
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