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Hypoxanthine guanine phosphoribosyltransferase partial deficiency
Kelley-Seegmiller syndrome (KSS) is the mildest form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see this term), a hereditary disorder of purine metabolism, and is associated with uric acid overproduction (UAO) leading to urolithiasis, and early-onset gout.
ORPHA:79233Classification level: Disorder
- HPRT deficiency, grade I
- HPRT partial deficiency
- HPRT-related gout
- HPRT-related hyperuricemia
- HPRT1 partial deficiency
- Hypoxanthine guanine phosphoribosyltransferase 1 partial deficiency
- Hypoxanthine guanine phosphoribosyltransferase deficiency, grade I
- Kelley-Seegmiller syndrome
- Prevalence: Unknown
- Inheritance: X-linked recessive
- Age of onset: All ages
- ICD-10: E79.8
- OMIM: 300323
- UMLS: C0268117
- MeSH: -
- GARD: -
- MedDRA: -
The exact prevalence is unknown but is probably underestimated due to misdiagnosis. KSS may represent about 15% of HPRT deficient patients.
Age of onset is usually in infancy but can also be in adulthood (up to 30 years). Males are generally affected and heterozygous females are carriers (usually asymptomatic). Patients are normal at birth. The first manifestation is the presence of orange crystals in diapers. Urolithiasis, uric acid nephropathy, urinary infections and renal obstruction are often the presenting symptoms. Gout may appear after puberty with acute arthritis or tophi. In contrast to Lesch-Nyhan syndrome (LNS; see this term), dystonia may be mild or even absent. Patients have normal intelligence associated with various degrees of attention deficit. Compulsive self-injurious behavior is absent.
The disease is caused by partial HPRT deficiency due to mutations in the HPRT1 gene (Xq26). Inheritance is X-linked recessive. UAO may be due to deficient recycling of purine bases with increased synthesis of purine nucleotides leading to hyperuricemia that increases the risk of UA crystal precipitation in tissues to form tophi, in joints leading to inflammatory processes and gouty arthritis, and renal UA excretion causing urolithiasis.
Diagnosis may be suspected when nephrolithiasis and/or obstructive nephropathy occur and is based on biochemical, enzymatic and molecular tests. Hyperuricemia and UAO are detectable in serum and urine. Plasmatic levels and urinary excretion of urate, hypoxanthine, and, to a lesser extent, xanthine are elevated. HPRT activity in hemolysate ranges from 0.5% to 10%.
Differential diagnosis includes glucose 6-phosphate dehydrogenase deficiency, Lesch-Nyhan syndrome and phosphoribosylpyrophosphate (PRPP) synthetase superactivity (see these terms).
Antenatal diagnosis is usually not required.
Management and treatment
UAO, nephrolithiasis, gouty arthritis and tophi can be managed with allopurinol, urine alkalinization (sodium bicarbonate or citrate) and generous hydration. Doses must be carefully adjusted to avoid xanthine lithiasis.
With appropriated treatment renal function remains stable and patients have a normal life expectancy.