Foundations · Year 1 · from Foundations
Case 2: Lesch-Nyhan Syndrome (HGPRT Deficiency)
Clinical Image
Source: Wikipedia - Lesch-Nyhan syndrome - CC BY-SA 3.0
Case Presentation
A 3-year-old boy is referred for evaluation of developmental delay, abnormal movements, and self-injurious behavior. He was noted to have hypotonia and developmental delay in infancy. He began biting his fingers at 18 months, requiring protective hand restraints. Physical examination reveals dystonia, choreoathetosis, and spasticity with hyperreflexia. His parents point out scarring on his lips and fingers from self-biting, and note he has had two episodes of kidney stones. Laboratory studies reveal markedly elevated serum uric acid at 12.5 mg/dL and elevated urinary uric acid excretion. 24-hour urine uric acid to creatinine ratio is significantly elevated. The clinical picture strongly suggests Lesch-Nyhan syndrome. Enzymatic assay confirms absent hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity, and genetic testing identifies a hemizygous mutation in HPRT1 on the X chromosome. Without HGPRT, salvage of purines is impossible, leading to accumulation of PRPP which drives excessive de novo purine synthesis. The resulting massive uric acid production causes gout and nephrolithiasis in childhood. The neurological manifestations (self-mutilation, dystonia, cognitive impairment) may relate to dopaminergic dysfunction, though the precise mechanism remains incompletely understood. He is treated with allopurinol for hyperuricemia and requires ongoing behavioral and physical management.
Key Learning Points
- HGPRT catalyzes the salvage of hypoxanthine and guanine to IMP and GMP; its deficiency causes accumulation of PRPP, which activates de novo purine synthesis
- The resulting purine overproduction leads to severe hyperuricemia with childhood gout and uric acid nephrolithiasis; allopurinol controls the metabolic consequences but not the neurological manifestations
- The compulsive self-injurious behavior (particularly biting lips and fingers) is a hallmark feature whose neurobiological basis likely involves abnormal dopamine neurotransmission