Uncovering Proteomic and Biochemical Alterations in Plasma from Lesch–Nyhan Disease Patients

TL;DR

This study explores proteomic and biochemical changes in the blood of Lesch–Nyhan disease patients to better understand the condition and potentially guide future treatments.

Contribution

This is the first proteomic study combined with clinical biochemistry and cytokine profiling in Lesch–Nyhan disease patients.

Findings

Plasma proteomics reveals potential biomarkers for monitoring Lesch–Nyhan disease progression.

Findings suggest that HPRT deficiency impacts broader cellular functions beyond purine metabolism.

Pro-inflammatory cytokine profiling highlights immune system involvement in Lesch–Nyhan disease.

Abstract

Lesch–Nyhan disease (LND) is an ultra-rare X-linked inborn error of metabolism caused by complete or partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), a key enzyme in the purine salvage pathway. This defect leads to uric acid overproduction and a broad spectrum of neurological and behavioral manifestations, whose severity depends on the degree of residual enzymatic activity. Although emerging evidence implicates HPRT deficiency in widespread cellular dysfunctions, particularly within midbrain dopaminergic neurons, the molecular mechanisms underlying the neurobehavioral phenotype of HPRT deficiency remain poorly understood and are not adequately explained by purine metabolism dysfunctions alone. Although proteomics represents a powerful approach for elucidating molecular alterations underlying disease, it has so far found only limited application in LND research. To address this gap, we provide here the first proteomic study combined with clinical biochemistry data and pro-inflammatory cytokines profiling of plasma samples from 29 HPRT deficient individuals (21 with classic LND and 8 with Lesch–Nyhan variants – LNV). We suggest that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.

The online version contains supplementary material available at 10.1007/s10571-025-01644-z.

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