Makindo Medical Notes

🧬 Lesch-Nyhan Syndrome (LNS) is a rare, X-linked disorder of purine metabolism caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This defect leads to severe hyperuricaemia, neurological dysfunction, and the striking behavioural hallmark of self-injurious behaviour (e.g., lip and finger biting). First described in 1964, it remains a classic example of how metabolic derangements can drive neuropsychiatric symptoms.

📖 About

• Inheritance: X-linked recessive – affects almost exclusively males 👦.
• Incidence: ~1 in 380,000 live births (rare, but important to recognise).
• Core triad: Hyperuricaemia 💎, neurological dysfunction 🧠, and self-injury 🤕.

🧬 Aetiology

• HGPRT deficiency impairs the salvage pathway of purine metabolism:
  • Hypoxanthine → IMP ❌
  • Guanine → GMP ❌
• Failure of salvage → ↑ breakdown of purines → uric acid overproduction.
• De novo purine synthesis is upregulated, compounding the problem.

⚙️ Pathophysiology

• Purinergic disruption: Loss of salvage → ↑ uric acid, ↓ IMP/GMP.
• Neurological basis: Thought to involve dopamine deficiency in basal ganglia → dystonia, spasticity, compulsive behaviours.
• Crystal deposition: Uric acid → gout, tophi, nephrolithiasis.
• Neuro-behavioural signature: Self-mutilation is unique and pathognomonic, beginning around age 2–3 years.

🩺 Clinical Features

• Early signs (infancy): Developmental delay, orange “sand-like” uric acid crystals in nappies 👶.
• Neurological: Severe motor dysfunction, spasticity, dystonia, choreoathetosis, intellectual disability.
• Behavioural: Self-biting (lips, tongue, fingers), head banging, aggression towards self and sometimes others – despite intact pain sensation.
• Renal: Uric acid nephrolithiasis, recurrent stones, gouty arthritis.
• Other: Anaemia, seizures, hearing loss may occur.

⚠️ Complications

• Chronic gouty arthritis and painful tophi 💎.
• Renal damage from urate stones → chronic kidney disease.
• Progressive neurological disability → wheelchair dependence.
• Recurrent infections, malnutrition, aspiration pneumonia → ↓ life expectancy (often <40 years).

🔎 Investigations

• Blood/Urine: ↑ uric acid levels (serum + urinary).
• Enzyme assay: HGPRT activity markedly reduced/absent (in fibroblasts or lymphocytes).
• Genetic testing: Mutation in HPRT1 gene confirms diagnosis; enables carrier testing.
• Imaging: Renal ultrasound/CT to detect stones.
• Neuroimaging: MRI may show basal ganglia abnormalities.

💊 Management

• Hyperuricaemia control: Allopurinol or febuxostat → prevents gout, kidney stones (but does not improve neuro symptoms).
• Neurological/Behavioural: Baclofen, benzodiazepines, gabapentin for dystonia/spasticity; behavioural strategies + protective devices (e.g., mouth guards, restraints when necessary).
• Pain management: NSAIDs for gouty pain, supportive analgesia for spasms.
• Supportive therapies: Physiotherapy, occupational therapy, speech therapy.
• Genetic counselling: Essential for families – female carriers have a 50% chance of passing the gene.
• Multidisciplinary care: Neurology, nephrology, psychiatry, rehab teams involved throughout life.

📌 Prognosis

Despite modern supportive care, life expectancy is reduced (20–40 years). Death often results from renal failure, respiratory infection, or complications of neurological disability. Quality of life can be improved with early recognition, aggressive uric acid control, and behavioural support.

📚 References

• Lesch-Nyhan Syndrome Overview – NCBI
• NORD: Lesch-Nyhan Syndrome
• Nyhan WL et al. (1964) – Original description of the syndrome.