Allopurinol is used in the treatment of gout and tumour lysis syndrome. In the biochemical treatment of Lesch-Nyhan syndrome, allopurinol effectively lowers uric acid but does NOT correct the neurological symptoms. This is because:

• A Allopurinol cannot cross the blood-brain barrier to reduce central uric acid
• B The neurological dysfunction is due to PRPP accumulation and abnormal purine signalling, not to uric acid toxicity per se ✓
• C Allopurinol is converted to allopurinol ribonucleotide by HGPRT, which is absent in Lesch-Nyhan syndrome
• D Allopurinol activates xanthine oxidase in the CNS through a paradoxical mechanism

Explanation

Allopurinol reduces uric acid production by inhibiting xanthine oxidase, which converts hypoxanthine to xanthine and xanthine to uric acid. This successfully normalises serum uric acid in Lesch-Nyhan syndrome. However, the neurological manifestations (choreoathetosis, self-mutilation, cognitive impairment) are not caused by uric acid itself but by the consequences of absent HGPRT—specifically, the dysregulation of PRPP, abnormal purine nucleotide pools, and the selective metabolic vulnerability of dopaminergic neurons in the basal ganglia. Reducing uric acid without restoring HGPRT activity or correcting intracellular purine homeostasis does not rescue neurological function. While allopurinol is indeed a substrate for HGPRT, this is a secondary observation and not the main reason for neurological persistence.

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

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Written and medically reviewed by the StethoPrep medical team.