A 4-year-old boy of Indian descent presents with orange-colored crystals in his diapers, developmental delay, and involuntary writhing movements. On examination, he has self-inflicted bite wounds on his lips and fingers. Genetic testing reveals a loss-of-function mutation in the HPRT1 gene. The enzyme marked **B** in the purine salvage pathway diagram is deficient. Which of the following best explains the hyperuricemia and gout observed in this patient?

Explanation

## Why option 1 is right The enzyme marked **B** is HGPRT (hypoxanthine-guanine phosphoribosyltransferase), which normally salvages hypoxanthine and guanine by converting them to IMP and GMP respectively using PRPP as the ribose donor. When HGPRT is deficient (Lesch-Nyhan syndrome, an X-linked recessive disorder caused by HPRT1 mutations), hypoxanthine and guanine cannot be recycled and instead accumulate. These purines are then shunted into the degradative pathway, where xanthine oxidase oxidizes them sequentially to xanthine and then uric acid, resulting in severe hyperuricemia, gout, and the characteristic orange uric acid crystals in diapers (Harper 32e Ch 33; Nelson 21e Ch 100). This is the pathognomonic biochemical signature of Lesch-Nyhan syndrome. ## Why each distractor is wrong - **Option 2**: APRT (adenine phosphoribosyltransferase, marked **C**) deficiency is a separate, much milder condition (adenine phosphoribosyltransferase deficiency) that causes 2,8-dihydroxyadenine kidney stones, not the severe hyperuricemia and neurologic phenotype of Lesch-Nyhan. The question specifically anchors on **B** (HGPRT), not **C**. - **Option 3**: Xanthine oxidase activity is not primarily dysregulated in HGPRT deficiency; rather, it is overwhelmed by excess substrate (hypoxanthine and guanine) that cannot be salvaged. Feedback inhibition by GMP and IMP is normal in Lesch-Nyhan patients, but these nucleotides are depleted because salvage is blocked, not because xanthine oxidase is overactive. - **Option 4**: De novo purine synthesis is actually increased in Lesch-Nyhan syndrome (due to loss of feedback inhibition by salvaged IMP and GMP), but the primary source of hyperuricemia is the failure of salvage, not excess de novo synthesis. De novo synthesis alone does not account for the magnitude of uric acid elevation observed. **High-Yield:** Lesch-Nyhan syndrome = HGPRT deficiency → loss of salvage → hypoxanthine and guanine shunted to xanthine oxidase → massive hyperuricemia + gout + orange uric acid crystals + pathognomonic self-mutilation (mechanism unclear, possibly dopamine dysregulation). Allopurinol treats hyperuricemia but NOT neurologic symptoms. [cite: Harper 32e Ch 33; Nelson 21e Ch 100]