Fragile X Mental Syndrome

Accounts for more cases of mental impairment in males than any condition except Down syndrome

Inherited as an X-linked condition

About 1 in 4000 males is affected

The CNS phenotype includes autism spectrum, impulsivity and aggressiveness, and repetitive behaviors

Heterozygous women have variable phenotypes that range from mental impairment to premature ovarian failure to essentially normal, in large part dependent on the number of repeated trinucleotides present

Affected males have

• Macro-orchidism (enlarged testes) after puberty

• Large ears and a prominent jaw, high-pitched voice, autistic characteristics, and mental impairment

• Evidence of a mild connective tissue defect, with joint hypermobility and mitral valve prolapse

Affected (heterozygous) women show no physical signs other than premature ovarian failure (early menopause), but they may have learning difficulties, anxiety, sensory issues, or frank retardation

Premutation carriers (men and women with 55–200 CGG repeats) may develop ataxia and tremor as older adults

Cytogenetic studies demonstrate a small gap, or fragile site, near the tip of the long arm of the X chromosome

Fragile site is due to expansion of a trinucleotide repeat (CGG) near a gene called FMR1

One FMR1 allele with ≥ 200 repeats results in mental impairment in virtually all men and learning difficulties in 60% of women

Clinical DNA diagnosis for the number of CGG repeats can be performed for any male or female who has unexplained mental impairment

Prenatal DNA diagnosis can be performed

No specific treatment has been developed

Valproic acid may reduce symptoms of hyperactivity and attention deficit, but standard therapies should be tried first