Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Fragile X Syndrome [Q99.2], FXPOI [28.3], FXTAS [G11.2]

OMIM numbers: 300624, 309550 (FMR1)

Dr. med. Imma Rost, Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh

Scientific Background

The fragile X syndrome is the most frequent monogenic inherited cause of intellectual disability. In contrast to other diseases with X chromosomal recessive inheritance, the fragile X syndrome exhibits characteristics such as healthy male conductors and in a proportion of affected females signs and symptoms similar to the ones found in male patients. The fragile X syndrome is caused by a CGG triplet repeat expansion in the 5' untranslated 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 with 50 to 55 repeats are defined as grey-zone allele (EMQN quality assessment scheme). This number of repeats exhibits a certain instability regardless of the gender of the carrier; however, no expansion to a full mutation has been observed in this range so far.

A premutation is the term for an allele with 56 to 200 CGG repeats. Premutations inherited from the mother are unstable, which usually leads to an expansion of the repeat to more than 200 triplets (full mutation). This expansion leads to methylation of cytosine residues of the repeat and adjacent regulatory elements which causes inhibition of transcription and therefore results in absence of the FMR1 gene product. Male premutation carriers will pass on the premutation stable to the next generation. Mothers of children with full mutations are obligate carriers of either a premutation or even a full mutation. The recurrence risk for an affected child is up to 50%, depending on the gender and the length of the mother's premutation.

Developmental delay, usually rather affecting speech than motoric development, is the first sign to occur in children with a full mutation. Children frequently are of above-average body length and have an above-average head circumference. Occasionally, signs of weakness of the connective tissue such as hyperextensibility of the joints and muscular hypotonia are observed. Characteristic features include hyperactivity and autistic behaviour. Apart from larger outer ears, phenotypical characteristics such as a long face and prominent chin are features typical for fragile X syndrome in adults; however, they are less marked in children. Men frequently show postpubertal macroorchidism. Female carriers of the full mutation may have a variety of signs and symptoms ranging from an inconspicuous phenotype (approx. 30%) to a severe intellectual disability similar to the one found in men. Approximately 20% of all female carriers of the premutation have a fragile X-associated primary ovarian insufficiency (FXPOI). Elderly, especially male carriers of the premutation show a progressive neurologic clinical picture in more than 30% of all cases, consisting of intention tremor, gait ataxia, parkinsonism, autonomic dysfunction and dementia. This has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS).