Description

• Fragile X syndrome (FXS) is the most common inherited form of mental retardation (also referred to as mental impairment) and is one of the leading known causes of autism (1).
• Among the genetic causes of mental impairment, FXS is the 2nd most common cause following Down syndrome.
• In addition to mental impairment, FXS is characterized by a group of symptoms that may include specific physical features, distinctive behavior patterns, defective speech and language, seizure disorder, and cognitive deficits (2).
• Synonym(s): Marker X syndrome; Martin-Bell syndrome; Escalante syndrome

Epidemiology

• Although this condition is seen in both sexes, males are usually more severely affected than females.
• Affected males almost always have mental impairment, mostly of moderate severity.
• Only 1/3–1/2 of affected females have mental impairment, usually in the mild-to-moderate range (2).

• FXS with full mutation is seen in 1:4,000 males and 1:8,000 females (3).
• FXS with premutation is seen in 1:800 males and 1:200 females (2).

Risk Factors

• This is an X-linked dominant disorder with variable penetrance.
• The syndrome is caused by an abnormal expansion of cytosine-guanine-guanine (CGG) on the fragile X mental retardation 1 (FMR1) gene. FMR1 normally synthesizes the fragile X protein (FMRP), but mutations in FMR1 lead to a lack of FMRP synthesis, which is important for normal brain development (4).
• The number of CGG repeats in the FMR1 gene are classified as:
  • Full mutation (>200 CGG repeats)
  • Premutation (∼6–200 CGG repeats)
• Most males with full mutation have mental impairment in addition to some form of the physical and behavioral features.
• Males with premutation have normal intelligence but have an increased risk for tremor-ataxia syndrome between age 50 and 60.
• Females with full mutation have an ~50% chance of having mental impairment in addition to some form of physical and behavioral features.
• Females with premutation have normal intelligence but have a 20% risk for premature ovarian failure.
• Since a male has only 1 X chromosome, it is never passed on to his son. He will pass the affected chromosome to all of his daughters.
• An affected female has a 50% chance of passing her affected chromosome to all of her children.

Commonly Associated Conditions

• Autistic spectrum disorder (3)
• Connective tissue manifestations, including flat feet and inguinal hernias (3)
• Mitral valve prolapse (develops during adolescence and adulthood) (3)
• Recurrent otitis media and sinusitis in childhood (3)
• Seizure disorder (15–20% for boys and 5% for girls) (4)
• Social phobias and other anxiety disorders (4)