A 6-year-old boy with intellectual disability, self-mutilation (lip/finger biting), choreoathetosis, and gout is found to have markedly elevated serum uric acid. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity in erythrocytes is virtually absent. The biochemical mechanism linking HGPRT deficiency to hyperuricemia is:

• A HGPRT deficiency increases PRPP availability, which drives increased de novo purine synthesis and ultimately excess uric acid ✓
• B Loss of PRPP salvage reduces pyrimidine synthesis, diverting PRPP to purine de novo synthesis
• C Lack of IMP recycling causes AMP and GMP depletion, stimulating purine catabolism to uric acid
• D HGPRT deficiency reduces feedback inhibition of glutamine PRPP amidotransferase (GPAT)

Explanation

HGPRT salvages hypoxanthine and guanine back to IMP and GMP respectively, consuming PRPP (5-phosphoribosyl-1-pyrophosphate) in the process. In Lesch-Nyhan syndrome (HGPRT deficiency), the salvage pathway is absent, so PRPP is not consumed by salvage and accumulates. Excess PRPP allosterically activates glutamine PRPP amidotransferase (the committed step of de novo purine synthesis), accelerating purine synthesis. The increased purines are ultimately catabolised to uric acid by xanthine oxidase. Additionally, IMP/GMP feedback on PRPP amidotransferase is reduced. The neurological features (self-mutilation, choreoathetosis) are not fully explained by hyperuricemia alone and reflect a specific role for HGPRT in dopaminergic neuron development.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.