What is Fragile X syndrome, its inheritance pattern, symptoms, treatment, and implications for pregnancy?

Fragile X Syndrome: Inheritance, Symptoms, Treatment, and Pregnancy Implications

Fragile X syndrome is the most common inherited cause of intellectual disability, resulting from a mutation in the FMR1 gene on the X chromosome that leads to absence of the fragile X mental retardation protein (FMRP), causing characteristic cognitive, behavioral, and physical features.

Genetics and Inheritance Pattern

Fragile X syndrome follows an X-linked inheritance pattern with unique characteristics:

• Located on chromosome Xq27.3 in the FMR1 gene 1
• Caused by expansion of CGG repeats in the 5' untranslated region of the FMR1 gene 1
• Classification based on repeat size:
  • Normal: <45 CGG repeats
  • Intermediate/gray zone: 45-54 repeats
  • Premutation: 55-200 repeats
  • Full mutation: >200 repeats (causes fragile X syndrome) 1, 2

The inheritance pattern has distinctive features:

• Full mutations are penetrant in all males and many females 1
• Expansion from premutation to full mutation almost exclusively occurs during maternal transmission 1
• The mutation is a multistep expansion occurring over generations 1
• Males with full mutations are typically more severely affected than females due to X-inactivation in females 2

Clinical Features and Symptoms

Cognitive and Behavioral Features

• Intellectual disability (variable severity, more severe in males) 1, 2
• Speech and language delays 3
• Learning difficulties 1, 3
• Attention deficits and hyperactivity 3, 4
• Anxiety 3, 4
• Impulsivity 4
• Autism spectrum features (poor eye contact, hand flapping, hand biting) 4
• Sleep problems 3

Physical Features

• Long face with prominent ears
• Macro-orchidism (enlarged testicles) in post-pubertal males
• Joint hypermobility
• Mitral valve prolapse
• High-arched palate 4

Premutation-Associated Conditions

Individuals with premutations (55-200 CGG repeats) may develop:

1. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) 1, 2:

   • Late-onset progressive neurological disorder
   • Intention tremor and ataxia
   • Progressive cognitive decline
   • Memory loss, anxiety, executive function deficits
   • Higher risk in males than females
   • Penetrance increases with age and premutation repeat length 1

2. Fragile X-associated Primary Ovarian Insufficiency (FXPOI) 1, 2:

   • Affects approximately 20% of female premutation carriers
   • Usually occurs with >80 CGG repeats
   • Leads to premature menopause and fertility issues 1

Diagnosis

Molecular genetic testing is the gold standard for diagnosis:

• DNA-based testing to determine CGG repeat number in FMR1 gene
• Southern blot analysis and PCR techniques are commonly used 1
• Testing is indicated for:
  • Individuals with intellectual disability, developmental delay, or autism
  • Family members of known carriers
  • Women with premature ovarian insufficiency
  • Older adults with progressive tremor/ataxia 1

Treatment Approaches

There is no cure for fragile X syndrome, but management focuses on symptom control:

1. Non-pharmacological interventions:

   • Speech and language therapy
   • Occupational therapy
   • Special education services
   • Behavioral therapy 3

2. Pharmacological treatments:

   • No FDA-approved medications specifically for fragile X syndrome
   • Symptom-based medication management:
     • Stimulants for ADHD symptoms
     • SSRIs for anxiety
     • Antipsychotics for aggression or severe behavioral issues
   • Targeted treatments showing promise:
     • Metformin
     • Sertraline
     • Cannabidiol 3

3. Emerging therapies:

   • Gene therapy approaches are in development and show potential for future treatment 3

Pregnancy and Genetic Counseling Implications

For women with fragile X premutations or full mutations:

1. Reproductive considerations:

   • Premutation carriers have increased risk of FXPOI, affecting fertility 1, 2
   • Genetic counseling is essential before pregnancy

2. Transmission risks:

   • Female premutation carriers have risk of expansion to full mutation when transmitted to offspring
   • Males with premutation typically pass the premutation (not full mutation) to all daughters
   • Males with full mutation do not typically transmit the full mutation as sperm usually carry premutations

3. Prenatal testing options:

   • Amniocentesis or chorionic villus sampling with FMR1 testing
   • Preimplantation genetic diagnosis for at-risk couples

4. Family screening:

   • Cascade testing of family members is recommended when a diagnosis is made
   • Allows identification of premutation carriers who may be at risk for FXTAS or FXPOI 1

Clinical Pearls and Pitfalls

• Fragile X syndrome must be considered in the differential diagnosis of any child with developmental delay, intellectual disability, or autism spectrum disorder 5
• Premutation carriers may appear unaffected in early life but develop FXTAS or FXPOI later in life 1, 2
• The severity of symptoms in females with full mutations is highly variable due to X-inactivation patterns
• Genetic counseling is complex due to the risk of expansion from premutation to full mutation during maternal transmission
• Limited awareness and poor access to genetic services remain significant challenges, particularly in resource-limited settings 6