Fragile X Mental Syndrome

Key Features

• 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

Clinical Findings

• 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

Diagnosis

• 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

Treatment

• No treatment directly addresses the underlying genetic perturbation

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