HPRT1 – Lesch-Nyhan Syndrome

Lesch-Nyhan syndrome is a severe X-linked recessive neurogenetic disorder caused by pathogenic variants in the hypoxanthine-guanine phosphoribosyltransferase gene (HPRT1). Affected individuals exhibit hyperuricemia, juvenile gout, nephrolithiasis, severe dystonia, choreoathetosis, intellectual disability, and compulsive self-mutilation. The causative defect in HPRT1 leads to complete loss of enzyme activity, disrupting purine salvage and resulting in uric acid overproduction and neurobehavioral manifestations characteristic of Lesch-Nyhan syndrome.

1. Clinical Validity

Definitive: Over 271 unrelated patients with >300 distinct HPRT1 mutations have been reported worldwide (PMID:11018746), with consistent X-linked recessive segregation and concordant biochemical and clinical findings. Multi-family studies demonstrate segregation of loss-of-function alleles with classical Lesch-Nyhan features and occasional female presentation due to skewed X-inactivation.

2. Genetic Evidence

Inheritance mode: X-linked recessive

Genetic evidence is strong: More than 300 unique variants—nonsense, frameshift, splice site, and large deletions—have been identified in over 271 patients, reaching the ClinGen genetic evidence cap (PMID:11018746). A recurrent hotspot at codon 51 (c.151C>T (p.Arg51Ter)) has been documented in multiple kindreds (PMID:2323782). Case reports describe prenatal and preimplantation diagnoses, germline mosaicism, and founder variants in diverse populations.

3. Functional / Experimental Evidence

Functional evidence is moderate: In vitro and cellular models recapitulate the purine salvage defect and neurological phenotype. HPRT1-deficient PC12 cells show impaired NGF-induced dopaminergic differentiation under purine-restricted conditions, implicating apoptosis of dopaminergic neurons in pathogenesis (PMID:9670994). Multi-omics of red blood cells from affected siblings reveals altered glycolysis, lipid metabolism, and redox homeostasis consistent with HPRT1 deficiency.

4. Conflicting Evidence

Partial HPRT1 deficiency (Kelley-Seegmiller syndrome) presents with hyperuricemia and mild neurologic signs, demonstrating genotype–phenotype variability. Female cases with skewed X-inactivation exhibit full Lesch-Nyhan phenotype despite heterozygosity, underscoring complexity in predicting clinical severity solely from mutation type.

5. Integration & Conclusion

The wealth of genetic and functional data establishes a definitive association between HPRT1 loss-of-function and Lesch-Nyhan syndrome. Despite extensive allelic heterogeneity, the pathogenic mechanism—complete enzyme deficiency leading to purine salvage failure—is consistent across variants. Genotype–phenotype correlations are imperfect, but enzyme activity assays and molecular diagnosis enable accurate confirmation, carrier detection, and prenatal testing.

Key Take-home: Genetic testing for HPRT1 should be performed in males with unexplained hyperuricemia, gout, nephrolithiasis, and neurobehavioral abnormalities to guide early diagnosis, management, and genetic counseling.

References

• Human genetics • 1990 • Hypoxanthine guanine phosphoribosyltransferase deficiency: nucleotide substitution causing Lesch-Nyhan syndrome identified for the first time among Japanese. PMID:2323782
• American journal of human genetics • 2000 • The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. PMID:11018746
• Journal of neuroscience research • 1998 • Impaired differentiation of HPRT-deficient dopaminergic neurons: a possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome. PMID:9670994

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