ESSENTIALS OF DIAGNOSIS
Expanded trinucleotide repeat (> 200) in the FMR1 gene.
Males: mental impairment and autism; large testes after puberty.
Females: learning disabilities or mental impairment; premature ovarian failure.
Late-onset tremor and ataxia in males and females with moderate trinucleotide repeat (55–200) expansion (premutation carriers).
This X-linked condition accounts for more cases of mental impairment in males than any condition except Down syndrome; about 1 in 4000 males is affected. The CNS phenotype includes autism spectrum, impulsivity and aggressiveness, and repetitive behaviors. The condition also affects intellectual function in females, although less severely and about 50% less frequently than in males. Affected (heterozygous) young women show no physical signs other than early menopause, but they may have learning difficulties, anxiety, sensory issues, or frank impairment. Affected males show macro-orchidism (enlarged testes) after puberty, large ears and a prominent jaw, a high-pitched voice, autistic characteristics, and mental impairment. Some males show evidence of a mild connective tissue defect, with joint hypermobility and mitral valve prolapse.
Women who are premutation carriers (55–200 CGG repeats) are at increased risk for premature ovarian insufficiency (FXPOI) and mild cognitive abnormalities. Male and female premutation carriers are at risk for mood and anxiety disorders and the development of tremor and ataxia beyond middle age (fragile X-associated tremor/ataxia syndrome, FXTAS). Changes in the cerebellar white matter may be evident on MRI before symptoms appear. Because of the relatively high prevalence of premutation carriers in the general population (1/130–1/600), older people in whom any of these behavioral or neurologic problems develop should undergo testing of the FMR1 locus.
The first marker for this condition was a small gap, or fragile site, evident near the tip of the long arm of the X chromosome. Subsequently, the condition was found to be due to expansion of a trinucleotide repeat (CGG) near a gene called FMR1. All individuals have some CGG repeats in this location, but as the number increases beyond 52, the chances of further expansion during spermatogenesis or oogenesis increase.
Being born with one FMR1 allele with 200 or more repeats results in mental impairment in most men and in about 60% of women. The more repeats, the greater the likelihood that further expansion will occur during gametogenesis; this results in anticipation, in which the disorder can worsen from one generation to the next.
DNA diagnosis for the number of repeats has supplanted cytogenetic analysis for both clinical and prenatal diagnosis. This should be done on any male or female who has unexplained mental impairment. Newborn screening based on hypermethylation of the FMR1 gene is being considered as a means of early detection and intervention.