Makindo Medical Notes

Related Subjects: |Osteoporosis |Autosomal Dominant |Autosomal Recessive |X Linked Recessive

🧬 Homocystinuria is caused by reduced activity of cystathionine β-synthase (CBS), leading to accumulation of homocysteine and methionine. This disrupts collagen cross-linking and predisposes to vascular thrombosis — the cardinal feature.

ℹ️ About

• 👤 Marfanoid habitus with tall build and long fingers
• ⚠️ High risk of arterial & venous thromboembolic events (MI, stroke, DVT)

🧪 Aetiology

• Deficiency of Cystathionine β-synthase (CBS enzyme)
• Homocysteine → accumulates and dimerises
• Results in vascular injury & thrombosis (often severe if plasma homocysteine >100 µmol/L)

🔬 Biochemistry

🧬 Genetics

• Inheritance: Autosomal recessive
• Mutation: CBS gene

🩺 Clinical Features

• 📚 Learning difficulties / developmental delay
• 📏 Tall, thin, marfanoid build with arachnodactyly, scoliosis, pectus deformities
• 👁️ Lens dislocation downwards (cf. Marfan’s = upwards)
• 🦴 Generalised osteoporosis, fractures
• ❤️ Early vascular events: MI, stroke, DVT before age 30
• 🧠 Seizures, intellectual disability (≈50%)
• 🌸 Fair skin, coarse hair (reduced melanin pathway)
• 🫁 Rare: spontaneous pneumothorax
• 🌀 Livedo reticularis (from venous thrombosis in dermal vessels)

🔍 Differential

• Marfan’s syndrome: upward lens dislocation, no thrombotic risk

🧾 Investigations

• 💧 Urine: positive cyanide-nitroprusside test (↑ homocysteine)
• 🩸 Plasma/urine amino acid screen: ↑ homocysteine & methionine
• 🧫 Fibroblast culture or liver biopsy: abnormal CBS enzyme

💊 Management

• 📌 High-dose Pyridoxine (Vitamin B6) (cofactor for CBS) — responsive in some cases
• 🥗 Low-methionine diet + betaine, folate, B12 supplementation (support remethylation pathways)
• 🍼 Early treatment essential to prevent intellectual disability

🩺 Case 1 — Child with Developmental Delay

A 6-year-old boy is brought with learning difficulties, clumsiness, and tall, thin build with long fingers resembling Marfan’s habitus. He has fair hair and blue eyes. Ophthalmology finds downward lens dislocation (ectopia lentis). Blood tests show elevated plasma homocysteine. Management: 💊 High-dose pyridoxine (B6) in responsive patients, plus folate and B12 supplementation. Restrict methionine intake, supplement cysteine. Avoid: ❌ Missing diagnosis by assuming Marfan’s; avoid unmonitored protein-rich diets that worsen methionine load.

🩺 Case 2 — Teen with Thromboembolism

A 16-year-old girl presents with sudden left leg swelling and pain. Doppler ultrasound shows extensive DVT. She has mild learning difficulties and a history of lens surgery for dislocation. Labs: markedly raised homocysteine levels confirming homocystinuria. Management: 🩺 Anticoagulation for thrombosis, long-term homocysteine-lowering therapy (pyridoxine, folate, B12, betaine). Genetic counselling. Avoid: ❌ Oestrogen-containing contraceptives (increase thrombotic risk). Avoid prolonged immobilisation without prophylaxis.