Fragile X Syndrome Overview
Fragile X syndrome (FXS) is an X-linked genetic disorder caused by mutations in the FMR1 gene located at Xq27.3, representing the most common inherited cause of intellectual disability and a leading genetic cause of autism spectrum disorder. 1
Genetic Basis
The molecular defect involves CGG trinucleotide repeat expansion in the 5' untranslated region of the FMR1 gene:
- Full mutation: >200 CGG repeats causes FXS through loss of fragile X mental retardation protein (FMRP) expression 1
- Premutation: 55-200 CGG repeats causes carrier status with distinct clinical syndromes 1, 2
- Normal range: <55 CGG repeats 1
The inheritance pattern is X-linked with multistep expansion occurring over generations, with the parent of origin for expansion to full mutation being female in virtually all cases 1
Clinical Manifestations in Full Mutation
Cognitive and Behavioral Features
Males with full mutations demonstrate complete penetrance for intellectual disability, while females show variable expression due to X-inactivation patterns: 3
- Intellectual disability: Ranges from mild to severe, with males typically more severely affected than females 3, 2
- Autism spectrum disorder: Occurs in approximately 20% of boys with FXS when evaluated by objective diagnostic criteria 3
- Behavioral phenotype: Includes characteristic but nonspecific physical features and behaviors 1
Medical Complications
Associated medical problems requiring surveillance include:
- Seizures: Develop in approximately 10-20% of individuals 3
- Recurrent otitis media and hearing difficulties: Necessitate audiologic assessment 3
- Ophthalmologic problems: Strabismus and refractive errors require evaluation 3
Premutation-Associated Conditions
Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)
Females with premutations, particularly those with >80 CGG repeats, face approximately 20% risk for premature ovarian insufficiency. 1, 3 Importantly, there is no evidence supporting an association between high normal and intermediate range FMR1 alleles with POI risk 1
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
FXTAS represents a late-onset, progressive neurodegenerative disorder affecting older males and females with premutations: 1, 3
- Core features: Intention tremor and ataxia accompanied by progressive cognitive and behavioral difficulties including memory loss, anxiety, reclusive behavior, executive function deficits, and dementia 1
- Risk factors: Higher in males carrying premutations compared to females, with penetrance increasing with age and premutation repeat length 1, 3
- Typical onset: Males over age 50 3
Premutation Cognitive Effects
Most individuals with premutations do not show FXS-related features; however, some with high repeat sizes (>100 repeats) may present with learning difficulties, emotional problems, or intellectual disability. 1, 3
Molecular Pathophysiology
FMRP functions as an RNA-binding protein and translation suppressor that regulates protein synthesis locally in dendrites in response to synaptic stimulation. 1 The absence of FMRP in FXS leads to exaggerated translation of certain messages, resulting in abnormally long and thin dendritic spines in cortical regions where excitatory synaptic transmission occurs 1
Diagnostic Considerations
The OMIM numbers for clinical reference are: *309550 (FMR1 gene), 300624 (fragile X mental retardation syndrome including FXPOI), and 300623 (FXTAS) 1
Molecular genetic testing of the FMR1 gene is one of the most frequently ordered genetic tests, requiring Southern blot analysis and polymerase chain reaction amplification methods including triplet repeat-primed and methylation-specific PCR. 1