Cause and inheritance
The FMR1 gene was identified in 1991. Typical alleles have up to about 45 CGG repeats; 55-200 is a premutation and more than 200 a full mutation, which methylates and silences the gene so the FMRP protein needed for synapse development is missing. Repeats can expand when passed from a mother carrying a premutation.
Symptoms
- Males usually have moderate intellectual disability; females, with two X chromosomes, are often more mildly affected.
- Gaze avoidance, anxiety, hyperactivity and sensory sensitivity, often overlapping with autism.
- A long face, large ears, flexible joints and enlarged testes after puberty.
- Premutation carriers risk primary ovarian insufficiency (FXPOI) and a late-onset tremor and ataxia syndrome (FXTAS).
Diagnosis and support
Named for a "fragile site" seen on chromosomes, it is now diagnosed by PCR and Southern blot DNA testing of repeat size. There is no cure; early intervention, speech and occupational therapy, behavioural support, targeted medication and family genetic counselling help.
References
- Verkerk, A. J., et al. (1991). Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell, 65(5), 905-914.
- Hagerman, R. J., et al. (2017). Fragile X syndrome. Nature Reviews Disease Primers, 3, 17065.
- Hunter, J. E., Berry-Kravis, E., Hipp, H., & Todd, P. K. (2019). FMR1 disorders. In GeneReviews. University of Washington, Seattle.