In Lesch-Nyhan syndrome, the deficiency of HGPRT leads to accumulation of which substrate that is then degraded to uric acid, causing hyperuricemia and neurological features?

• A Orotic acid and orotidine
• B PRPP accumulates, driving de novo purine synthesis excess
• C Hypoxanthine and guanine are not salvaged and are oxidized to uric acid ✓
• D Adenosine deaminase excess degrades adenosine to inosine and then uric acid

Explanation

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) normally salvages hypoxanthine → IMP and guanine → GMP. In Lesch-Nyhan syndrome, HGPRT deficiency means hypoxanthine and guanine cannot be salvaged and are instead oxidized by xanthine oxidase to xanthine and then to uric acid. Additionally, PRPP (phosphoribosyl pyrophosphate) accumulates because it is not consumed by the salvage pathway, further driving de novo purine synthesis. However, option B only captures one aspect; the direct cause of hyperuricemia is the oxidation of unsalvaged hypoxanthine and guanine (option C). Orotic acid accumulation (option A) occurs in UMP synthase deficiency (hereditary orotic aciduria).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.