fragile X syndrome
Fragile X syndrome is the most common inherited cause of cognitive disability and is the result of the mutation in the fragile X mental retardation 1 (FMR1) gene.
Epidemiology
Although the degree of cognitive disability is typically more severe in males with fragile X syndrome, females can also be affected. The estimated frequency of fragile X syndrome is 1/4000 males and 1/7000 females .
Clinical presentation
Affected individuals demonstrate a variety of cognitive disabilities and physical changes .
- cognitive
- variable cognitive disability ranging from mild to severe
- autistic features
- seizures
- Prader-Willi phenotype (not Prader-Willi syndrome which is genetically distinct)
- musculoskeletal
- hypermobility
- velvet-like skin
- cardiovascular vascular
- facial dysmorphism
- long narrow faces
- large ears
- reproductive system
- macroorchidism (males)
Pathology
The underlying genetic abnormality is an expansion of a trinucleotide repeat (CGG) in the 5` untranslated region fragile X mental retardation 1 (FMR1) gene that encodes for the fragile X mental retardation protein (FMRP) . This repeat is inherently unstable and can result in an expansion of the repeat during maternal transmission .
Based on the number of repeats FMR1 genes can be divided into three groups that correlate with phenotype .
- 5-54 repeats: normal population
- 55-200 repeats: premutation
- >200 repeats: fragile X syndrome
Permutation
When 55-200 repeats are present there are excessive levels of FMR1 mRNA transcription but despite this, the actual levels of FMRP are reduced . Generally, most premutation carriers are phenotypically normal, however, approximately 25% demonstrate some subtle physical changes . Emotional difficulties are also reported . Specific sex-dependent phenotypic manifestations are also encountered:
- males: fragile X-associated tremor/ataxia syndrome
- females: primary ovarian insufficiency
- found in approximately 20% of female premutation carriers
Fragile X syndrome
Once more than 200 repeats are present a cascade of events takes place resulting in the eventual methylation of the promoter region of the FMR1 gene which in turn silences the gene resulting in a lack of FMRP and resultant fragile X syndrome .
Radiographic features
Imaging will depend on the specific manifestations of the syndrome in an individual (see above).
Treatment and prognosis
At this time there are no accepted gene therapies or FMRP replacement therapies available, although both approaches are being researched.
Management is therefore targetted at the various manifestations of fragile X syndrome.
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