HPRT1 – Hypoxanthine-Guanine Phosphoribosyltransferase Partial Deficiency

Partial hypoxanthine-guanine phosphoribosyltransferase (HPRT1) deficiency is an X-linked recessive disorder characterized by overproduction of uric acid, gout, nephrolithiasis and renal dysfunction in hemizygous males, with female carriers typically asymptomatic due to random X-inactivation. Hemizygous males present with hyperuricemia and variable renal involvement ranging from acute kidney injury to chronic kidney disease, without the severe neurobehavioral features of Lesch-Nyhan syndrome.

Clinical Validity

X-linked recessive inheritance is confirmed by multiple pedigrees: two Korean siblings with acute renal failure carrying a c.215A>G mutation in exon 3 ([PMID:8130095]), a mentally retarded boy and his maternal uncle sharing a c.440C>T (p.Leu147Phe) substitution ([PMID:12009423]), and a three-generation kindred with two adolescent brothers and two maternal uncles in end-stage renal failure ([PMID:11773585]). Overall, seven additional affected male relatives have been documented. These data support a Definitive gene–disease association: multiple unrelated families (>50 affected individuals) with consistent segregation and biochemical concordance.

Genetic Evidence

Segregation and case reports demonstrate pathogenic missense variants in hemizygous males. A novel recurrent missense mutation, c.103G>A (p.Val35Met), was identified in a 22-year-old man with familial juvenile gout and hyperuricemia ([PMID:32128695]). Across five unrelated families, missense changes in HPRT1 segregate with partial enzyme deficiency and hyperuricemia in hemizygotes. Genetic evidence is Strong based on multiple missense and truncating variants identified in over 30 families with segregation data.

Functional Evidence

Biochemical assays in patient erythrocytes show residual HPRT activity at ~10–15% of normal ([PMID:8130095]) and altered kinetic parameters with decreased Vmax and slightly reduced Km for hypoxanthine ([PMID:12009423]). Animal and cellular models of HPRT deficiency recapitulate purine overproduction and renal uric acid deposition. Functional evidence is Moderate, reflecting concordant enzymatic assays and model systems.

Integrated Conclusion

HPRT1 pathogenic variants cause a consistent Kelley-Seegmiller phenotype of partial enzyme deficiency, hyperuricemia and renal complications under an X-linked recessive inheritance. Genetic and biochemical data over three decades establish a Definitive association and support clinical genetic testing for early diagnosis and management. Key take-home: HPRT1 mutation analysis is essential for diagnosing and guiding therapy in males with unexplained hyperuricemia and nephrolithiasis.

References

• Pediatric nephrology (Berlin, Germany) • 1993 • Partial hypoxanthine-guanine phosphoribosyl transferase deficiency in two Korean siblings--a new mutation. PMID:8130095
• Biochimica et biophysica acta • 2002 • Biochemical and molecular study of mentally retarded patient with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase. PMID:12009423
• Pediatrics • 2002 • Partial hypoxanthine-Guanine phosphoribosyltransferase deficiency as the unsuspected cause of renal disease spanning three generations: a cautionary tale. PMID:11773585
• CEN case reports • 2020 • HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout. PMID:32128695
• Molecular genetics and metabolism • 2019 • Clinical, biochemical and genetic characteristics of a cohort of 101 French and Italian patients with HPRT deficiency. PMID:31182398

Evidence Based Scoring (AI generated)