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Key Features

  • Accounts for more cases of retardation 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 retardation 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 retardation

    • 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 retardation 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 retardation

  • Prenatal DNA diagnosis can be performed

Treatment

  • No specific treatment has been developed

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

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