In gout, which enzyme deficiency leads to massive overproduction of uric acid and hyperuricemia due to inability to salvage hypoxanthine and guanine?

Explanation

## HGPRT Deficiency and Hyperuricemia **Key Point:** Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency prevents salvage of hypoxanthine and guanine, forcing all purine catabolism through oxidation to uric acid, causing severe hyperuricemia and gout. ### Mechanism of Uric Acid Overproduction ```mermaid flowchart TD A[Hypoxanthine + Guanine]:::outcome --> B{HGPRT present?}:::decision B -->|Yes| C[Salvage pathway<br/>IMP + GMP]:::action B -->|No| D[Oxidation pathway<br/>Xanthine oxidase]:::action C --> E[Nucleotide reuse<br/>Low uric acid]:::outcome D --> F[Xanthine → Uric acid]:::action F --> G[Severe hyperuricemia<br/>Gout + kidney stones]:::urgent ``` ### HGPRT Deficiency Syndromes | Condition | HGPRT Activity | Uric Acid | Clinical Features | | --- | --- | --- | --- | | **Lesch-Nyhan Syndrome** | <1% | Massive ↑↑↑ | Gout in infancy, kidney stones, neurological (dystonia, spasticity, self-injury) | | **HGPRT Partial Deficiency** | 10–50% | Moderate ↑ | Gout in childhood/adolescence, no neurological symptoms | | **Normal** | 100% | Normal | Salvage pathway functional | ### Why HGPRT Deficiency Causes Gout 1. **Salvage pathway blocked** — hypoxanthine and guanine cannot be recycled into IMP and GMP. 2. **Forced oxidation** — all purines are oxidized by xanthine oxidase to uric acid. 3. **Increased PRPP availability** — loss of salvage feedback inhibition causes PRPP to accumulate and drive de novo purine synthesis even faster. 4. **Dual mechanism** — both increased catabolism (oxidation) AND increased synthesis (de novo) lead to massive uric acid production. **High-Yield:** Lesch-Nyhan syndrome is the **complete** HGPRT deficiency (<1% activity). Partial HGPRT deficiency presents as gout without the severe neurological manifestations. Both are X-linked recessive. **Mnemonic:** **HGPRT = Hypoxanthine-Guanine salvage Pathway Recycles Thymidine** (mnemonic for what it does) — when deficient, purines are NOT salvaged, so they are oxidized to uric acid. **Clinical Pearl:** Patients with Lesch-Nyhan syndrome present with gout and kidney stones in infancy (age 6–12 months), making it one of the earliest presentations of gout in pediatric practice. The neurological symptoms (choreoathetosis, self-mutilation) develop later and are thought to be due to dopamine deficiency in the basal ganglia.