Introduction

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the leading known genetic cause of autism spectrum disorder. It affects approximately 1 in 4,000 males and 1 in 8,000 females.

Key Points

• Most common inherited intellectual disability
• X-linked dominant inheritance pattern
• Caused by FMR1 gene mutation
• Variable expression in females
• Associated with autism spectrum features

Clinical Features

Physical Characteristics

• Facial Features:
  • Long, narrow face
  • Prominent forehead and chin
  • Large protruding ears
  • High-arched palate
• Post-pubertal Features:
  • Macroorchidism in males
  • Joint hypermobility
  • Soft, hyperextensible skin

Neurodevelopmental Features

• Cognitive:
  • Intellectual disability (mild to severe)
  • Speech and language delays
  • Processing difficulties
  • Working memory deficits
• Behavioral:
  • Attention deficit and hyperactivity
  • Anxiety and mood disorders
  • Autistic-like behaviors
  • Social avoidance
  • Sensory integration issues

Diagnosis

Molecular Testing

• Primary Tests:
  • PCR analysis for FMR1 CGG repeat number
  • Southern blot analysis
  • Methylation testing
• Categories of Results:
  • Normal: 5-44 CGG repeats
  • Intermediate: 45-54 repeats
  • Premutation: 55-200 repeats
  • Full mutation: >200 repeats

Screening Considerations

• Newborn screening not currently routine
• Consider testing in:
  • Developmental delay/intellectual disability
  • Autism spectrum features
  • Family history of FXS
  • Premature ovarian insufficiency

Management

Educational Interventions

• Early intervention services
• Special education support
• Speech and language therapy
• Occupational therapy
• Physical therapy
• Social skills training

Medical Management

• Behavioral Interventions:
  • Applied behavior analysis (ABA)
  • Cognitive behavioral therapy
  • Social skills training
• Medication Management:
  • Stimulants for ADHD symptoms
  • SSRIs for anxiety/mood disorders
  • Antipsychotics for aggression/irritability
  • Melatonin for sleep disorders

Regular Monitoring

• Annual developmental assessments
• Regular hearing evaluations
• Cardiac assessment if indicated
• Ophthalmological examination
• Orthopedic evaluation if needed

Genetics & Molecular Basis

Molecular Genetics

• Gene Location: Xq27.3
• Gene Product: FMRP (Fragile X Mental Retardation Protein)
• Function:
  • RNA binding protein
  • Regulates synaptic plasticity
  • Controls protein synthesis
  • Essential for normal neural development

Inheritance Pattern

• X-linked dominant inheritance
• Variable expressivity in females
• Complex inheritance patterns due to premutation effects
• Anticipation phenomenon

Associated Conditions

Premutation Carriers

• FXTAS (Fragile X-associated Tremor/Ataxia Syndrome):
  • Late-onset neurological condition
  • Progressive cerebellar ataxia
  • Intention tremor
  • Cognitive decline
• FXPOI (Fragile X-associated Primary Ovarian Insufficiency):
  • Early menopause
  • Reduced fertility
  • Hormonal implications

Medical Comorbidities

• Seizures (15-20% of males)
• Strabismus
• Recurrent otitis media
• Gastrointestinal problems
• Sleep disorders

Prognosis & Counseling

Long-term Outcomes

• Variable prognosis based on gender and mutation size
• Most individuals require lifelong support
• Many achieve some degree of independence
• Normal life expectancy

Family Support

• Genetic counseling
• Family support groups
• Educational advocacy
• Transition planning
• Adult care considerations