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Lesch-Nyhan syndrome

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Definition: inherited genetic disorder characterized by impaired purine salvage pathway, resulting in an overproduction of uric acid

Epidemiology

Etiology

Pathophysiology

Purine Salvage Pathway

  • Goal: Recycle free purine bases to reform nucleotides, conserving energy.
  • Key Enzymes:
    • HGPRT (Hypoxanthine-guanine phosphoribosyltransferase):
      • Converts Hypoxanthine → IMP.
      • Converts Guanine → GMP.
    • APRT (Adenine phosphoribosyltransferase):
      • Converts Adenine → AMP.
  • Lesch-Nyhan Syndrome: X-linked recessive deficiency of HGPRT.
    • Patho: Inability to salvage hypoxanthine and guanine leads to their degradation, causing excess uric acid production. Also leads to ↑ de novo purine synthesis due to ↑ PRPP levels.
    • Presentation (HGPRT):
      • Hyperuricemia (gout, “orange sand” [sodium urate crystals] in diaper).
      • Gout.
      • Pissed off (aggression, self-mutilation).
      • Retardation (intellectual disability).
      • Tonia (dystonia).

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Clinical features

  • Renal / Urologic:
    • “Orange sand” in diapers (sodium urate crystals; often the earliest sign).
    • Uric acid nephrolithiasis hematuria, dysuria, UTIs, or renal colic.
  • Neurologic: c
    • Early: Hypotonia, poor head control, developmental delay.
    • Late (by age 1–2): Extrapyramidal signs (dystonia, choreoathetosis), pyramidal signs (spasticity, hyperreflexia, clonus, extensor plantar responses).
    • Often initially misdiagnosed as cerebral palsy.
  • Behavioral / Cognitive:
    • Intellectual disability (mild to moderate).
    • Self-mutilation (hallmark; onset typically at age 2–3): Lip and finger biting, head-banging, gouging. c
    • Aggression toward others, verbal outbursts.
  • Musculoskeletal:
    • Gouty arthritis and tophaceous deposits (later in childhood/adolescence).

Diagnostics

  • Hyperuricemia
  • ↓ HGPRT activity
  • ↑ Phosphoribosyl pyrophosphate amidotransferase (converts PRPP to GMP and AMP)
  • Macrocytosis (megaloblastic anemia may occur)

Differential diagnostics

  • Autism Spectrum Disorder (ASD):
    • Shared: Developmental delay, social/behavioral abnormalities, head-banging.
    • Diff: ASD lacks motor signs (choreoathetosis), severe tissue-destructive self-mutilation (lip/finger biting), and hyperuricemia.

Treatment

  • Reduce uric acid levels:
    • Allopurinol (first-line)
    • Febuxostat (second-line)
    • Low-purine diet

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