Makindo Medical Notes

📖 About

• Fragile X Syndrome is an X-linked dominant genetic disorder.
• 🧠 It is the most common inherited cause of intellectual disability and autism spectrum disorder.
• 👨 Males are more severely affected (single X chromosome)
• 👩 females can be carriers or show milder–moderate features.
• 📊 Worldwide prevalence: ~1 in 4,000 males, 1 in 8,000 females.

🧬 Aetiology

• Caused by an expansion of CGG trinucleotide repeats in the FMR1 gene on the X chromosome.
• This leads to ↓ expression of Fragile X Mental Retardation Protein (FMRP), essential for synaptic development and plasticity.
• 🔑 Normal: <45 repeats; Premutation: 55–200; Full mutation: >200 → symptomatic Fragile X.
• Variable expressivity – clinical severity depends on repeat size and methylation status.
• Premutation carriers are at risk of:
  • Fragile X-associated tremor/ataxia syndrome (FXTAS) in older males.
  • Primary ovarian insufficiency in females.

👩‍⚕️ Clinical Features

• Facial features: Long narrow face, large protruding ears, prominent jaw (prognathism), high-arched palate.
• Cognition & behaviour: Intellectual disability, speech delay, learning difficulties, autistic-like features (poor eye contact, social anxiety, repetitive behaviour, hand-flapping, self-injury).
• Hyperactivity/ADHD: Impulsivity, attention deficit; seizures may occur.
• Neuromuscular: Hypotonia, hyperextensible joints, frequent otitis media, strabismus.
• Cardiac: Mitral valve prolapse, a common feature.
• Reproductive: Macroorchidism (large testes) in post-pubertal males – hallmark sign.
• Developmental delays: Motor delay, toe-walking, clumsiness.

🧪 Investigations

• Genetic testing: Gold standard – PCR + Southern blot to determine CGG repeat number in FMR1.
• Antenatal diagnosis: Via chorionic villus sampling or amniocentesis if family history known.
• Family screening: Identifies carriers → allows genetic counselling.

⚕️ Management

• No cure – focus is on symptom control, early interventions, and support.
• Behavioural therapies: Early speech, occupational, and behavioural therapy improve outcomes.
• Medications:
  • SSRIs for anxiety/mood.
  • Stimulants (e.g., methylphenidate) for ADHD features.
  • Anticonvulsants for seizures.
  • Antipsychotics/lithium for behavioural dysregulation.
• Educational support: Tailored special needs education, structured routines.
• Family support: Genetic counselling essential for at-risk families.

💡 Exam Pearls

• 🔑 Think Fragile X in a boy with autism, large ears, and macroorchidism.
• 📊 Differentials: Autism spectrum disorder, ADHD, Prader–Willi syndrome.
• 👩 Premutation carriers → risk of early menopause (primary ovarian insufficiency).
• 👨 Older male premutation carriers → tremor/ataxia syndrome (FXTAS).

📚 References

• UK NICE guidelines: Genetics & rare conditions
• GeneReviews – Fragile X Syndrome
• BMJ Best Practice – Fragile X Syndrome

🧾 Clinical Case Example – Fragile X Syndrome

A 10-year-old boy is referred for developmental delay and learning difficulties. His teacher reports poor concentration, social anxiety, and repetitive hand-flapping behaviours. Exam: long narrow face, large ears, hyperextensible joints, and macro-orchidism. Family history reveals maternal uncles with intellectual disability. 🧪 Genetic testing confirms a CGG trinucleotide repeat expansion in the FMR1 gene on the X chromosome. 👉 Diagnosis: Fragile X syndrome. 👉 Management: Supportive – speech therapy, behavioural interventions, educational support, and genetic counselling for family.