Fragile X Syndrome

Genetic defect and pathogenesis

• The FMR1 gene contains CGG repeats in its 5′ untranslated region.
• Normal allele: about 6-55 CGG repeats.
• Premutation: 55-200 repeats. Carriers are usually not affected with classical FXS.
• Full mutation: usually >200 repeats, sometimes expanding to several thousand.
• The full mutation causes hypermethylation of the 5′ region and promoter of FMR1.
• This epigenetically silences transcription of FMR1, resulting in deficiency of FMRP (fragile X messenger ribonucleoprotein).
• FMRP normally regulates transport and translation of mRNAs at neuronal synapses. Its loss leads to abnormal synaptic development and neurodevelopmental impairment.

Inheritance and anticipation

• Shows an unusual X-linked inheritance pattern with anticipation: disease becomes more severe or more frequent in later generations because the CGG repeat expands.
• Premutations commonly expand to full mutations during maternal transmission/oogenesis, not during spermatogenesis.
• Thus, a carrier woman can have sons with a full mutation who are severely affected.
• Females are less severely affected because of the second normal X chromosome; phenotype varies with skewed X-inactivation.

Clinical features

• Moderate to severe intellectual disability
• Delayed speech and developmental delay
• Autism spectrum disorder or autistic behavior
• Behavioral abnormalities, including hyperactivity, anxiety, poor eye contact, and hand flapping
• Long narrow face
• Large, protruding ears
• Macroorchidism after puberty
• May have connective-tissue manifestations such as joint laxity and mitral valve prolapse

• About 30%-50% of female full-mutation carriers may show intellectual disability or behavioral features, usually milder than in males.

Fragile site and diagnosis

Premutation-associated disorders

1. Fragile X-associated tremor/ataxia syndrome (FXTAS)
   • Mainly affects older premutation-carrying men
   • Intention tremor, cerebellar ataxia, and possible parkinsonism
   • Associated with intranuclear inclusions in the nervous system
2. Fragile X-associated primary ovarian insufficiency
   • Occurs in some female premutation carriers
   • Premature ovarian failure, reduced fertility, early menopause

Robbins key points

• Mutation: CGG-repeat expansion in noncoding 5′ UTR of FMR1
• Full mutation mechanism: promoter hypermethylation -> FMR1 silencing -> loss of FMRP
• Inheritance: X-linked with maternal expansion and anticipation
• Classic phenotype: intellectual disability, autism-related manifestations, long face, large ears, macroorchidism
• Premutation: toxic RNA gain-of-function causing FXTAS and primary ovarian insufficiency