FXS is the most prevalent inherited cause of mild-to-severe intellectual disability and the most common monogenic cause of autism spectrum disorder.

Overview

• Fragile X Syndrome (FXS), also known historically as Martin-Bell syndrome, is a non-Mendelian trinucleotide repeat disorder.
• Most common inherited cause of mild-to-severe intellectual disability and the leading monogenic cause of autism spectrum disorder.
• Accounts for about half of X-linked intellectual disability cases and is second to trisomy 21 in mental impairment causes.

Etiology

• Genetic Basis: Caused by an expansion of the CGG triplet repeat in the FMR1 gene on the X chromosome, leading to reduced or absent fragile X mental retardation protein (FMRP).
  • Normal: 5–44 repeats
  • Intermediate: 45–54 repeats
  • Premutation: 55–200 repeats
  • Full mutation: >200 repeats (results in hypermethylation and silencing of the gene).
• X-Linked Dominant Inheritance:
  • Variable expressivity and incomplete penetrance.
  • Females have a milder phenotype due to the protective effect of the second X chromosome.

Epidemiology

• Prevalence:
  • 1 in 7,000 males and 1 in 11,000 females have the full mutation.
  • Carrier frequency: 1 in 130–250 females and 1 in 250–800 males.
• Carrier prevalence varies by population, with some regions (e.g., Colombia) reporting significantly higher rates.

Pathophysiology

• Loss of FMRP disrupts synaptic plasticity, neuronal connectivity, and normal regulation of protein translation.
• Key physiological effects:
  • Increased neuronal excitation
  • Reduced GABAergic activity
• Brain-specific impacts:
  • Decreased cerebellar size
  • Hypoplasia of the cerebellar vermis
  • Enlargement of the caudate nucleus

Clinical Presentation

1. Physical Features:
   • Long, narrow face with prominent jaw and forehead
   • Large, protruding ears
   • Hyperextensible fingers and joints
   • Macroorchidism in post-pubertal males
2. Developmental and Behavioral Features:
   • Intellectual disability (moderate to severe in males)
   • Autism spectrum disorder (features in 30% of cases)
   • ADHD symptoms, anxiety, obsessive-compulsive traits
   • Delayed speech and language development
3. Neurological Symptoms:
   • Seizures (common)
   • Hypotonia
   • Sleep disturbances
4. Associated Conditions:
   • Chronic otitis media
   • Strabismus, dental crowding, pes planus
   • Frequent infections (e.g., sinusitis, otitis media)

Diagnostic Evaluation

• Molecular Testing: Preferred over cytogenetics.
  • PCR to determine CGG repeat number.
  • Southern blot to assess methylation status.
• Associated Investigations:
  • EEG for seizures
  • Sleep studies for obstructive apnea
  • Imaging for associated abnormalities (e.g., urinary tract, brain MRI for structural concerns).

Management

• Supportive Therapies:
  • Early interventions: speech therapy, occupational therapy, behavioral therapy, and special education.
  • Psychiatric support for mood disorders, anxiety, and aggression.
  • Nutritional counseling to manage obesity risks.
• Pharmacological Treatments:
  • Stimulants for ADHD-like symptoms.
  • Antidepressants for anxiety and mood regulation.
  • Antipsychotics (e.g., risperidone, aripiprazole) for severe behavioral issues.
  • Anticonvulsants for seizure control.
  • Experimental treatments: Metformin and transdermal cannabidiol show promise.
• Family Support:
  • Genetic counseling to address reproductive risks.
  • Caregiver assistance to reduce stress and improve coping strategies.

Prognosis

• Life expectancy is generally normal but depends on associated conditions.
• Quality of life is variable, influenced by the severity of intellectual disability and comorbidities like autism and seizures.

Complications

• Intellectual disabilities, chronic ear infections, seizures, and connective tissue abnormalities.
• Behavioral issues can lead to significant social and academic challenges.

Differential Diagnosis

• Includes conditions with overlapping symptoms, such as:
  • Sotos syndrome
  • Prader-Willi syndrome
  • Rett syndrome
  • Autism
  • Trisomy 21

Consultations

• Geneticists and neurodevelopmental specialists (e.g., pediatric neurologists).
• Occupational, speech, and behavioral therapists.
• Psychiatry for mood and behavioral issues.
• Specialists for associated conditions (e.g., ophthalmologists for strabismus, surgeons for hernias).

Education and Interprofessional Care

• Emphasis on parent education about FXS progression, complications, and reproductive risks.
• Advocacy for universal newborn screening to enhance early detection.
• Collaborative healthcare team involving pediatricians, geneticists, therapists, and counselors for holistic care.