Fragile X syndrome
📖 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
🧾 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.
