A 3-year-old boy presents with choreoathetosis, self-mutilation, hyperuricemia, and intellectual disability. Enzyme assay shows absent HGPRT (hypoxanthine-guanine phosphoribosyltransferase) activity. The mechanism by which HGPRT deficiency causes neurological dysfunction is best explained by:

• A Accumulation of PRPP drives excessive de novo purine synthesis, with hypoxanthine and xanthine being neurotoxic
• B Uric acid crystals deposit in caudate nucleus causing mechanical damage
• C PRPP deficiency secondary to HGPRT loss impairs pyrimidine synthesis needed for myelination
• D Dopaminergic neurons in basal ganglia depend heavily on the salvage pathway and are selectively vulnerable to HGPRT deficiency ✓

Explanation

HGPRT catalyses the salvage of hypoxanthine and guanine back to IMP and GMP using PRPP. In its absence, PRPP accumulates and drives unregulated de novo purine synthesis, generating excess uric acid. Neurologically, dopaminergic neurons in the basal ganglia (striatum) have exceptionally high purine recycling needs and rely almost exclusively on the salvage pathway rather than de novo synthesis. This selective metabolic dependence makes them disproportionately vulnerable to HGPRT deficiency, explaining the characteristic neurological features of Lesch-Nyhan syndrome (spasticity, choreoathetosis, self-mutilation). Uric acid crystals do not penetrate the blood-brain barrier in significant amounts, and PRPP is actually increased, not decreased.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.