Alternative titles; symbols
SNOMEDCT: 238007004; ORPHA: 79233; DO: 0112127;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq26.2-q26.3 | Hyperuricemia, HRPT-related | 300323 | X-linked recessive | 3 | HPRT1 | 308000 |
A number sign (#) is used with this entry because HPRT-related hyperuricemia (HRH), also known as Kelley-Seegmiller syndrome, is caused by mutation in the HPRT gene (308000) that results in partial deficiency of hypoxanthine guanine phosphoribosyltransferase.
Virtually complete deficiency of HPRT residual activity is associated with the Lesch-Nyhan syndrome (LNS; 300322), whereas partial deficiency (at least 8%) is associated with the Kelley-Seegmiller syndrome. LNS is characterized by abnormal metabolic and neurologic manifestations. In contrast, Kelley-Seegmiller syndrome is usually associated only with the clinical manifestations of excessive purine production. Renal stones, uric acid nephropathy, and renal obstruction are often the presenting symptoms of Kelley-Seegmiller syndrome, but rarely of LNS. After puberty, the hyperuricemia in Kelley-Seegmiller syndrome may cause gout (summary by Zoref-Shani et al., 2000).
In 5 male patients with gout, Kelley et al. (1967) found a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase. Two brothers in 1 family were 24 and 11 years old; three brothers in another family were 42, 49, and 55 years old. In the first family, nephrolithiasis began at age 6 or 7, followed in one by gouty arthritis at age 13. In the 3 brothers, acute gouty arthritis began between ages 20 and 31 and 2 had had recurrent nephrolithiasis. The 2 brothers of the first family had spinocerebellar derangement distinct from the neurologic disorder of the Lesch-Nyhan syndrome. The characteristics of the enzyme were the same in each family but different between families. The differences concerned relative activities for guanine and hypoxanthine and heat stability.
McDonald and Kelley (1971) presented evidence of genetic heterogeneity in the Lesch-Nyhan syndrome. In the patient they reported, HPRT showed altered kinetics. Among 425 cases of hyperuricemia with gout or uric acid stone or both, Yu et al. (1972) found 7 with partial HPRT deficiency and 5 of these were members of one family.
Andres et al. (1987) reported the case of a 12-year-old boy who presented with acute renal failure accompanied by a disproportionate increase of serum uric acid level and massive uric acid crystalluria. After alkalinization and allopurinol therapy, serum uric acid and renal function returned to normal. HPRT deficiency was found as the basis of the abnormality.
Zoref-Shani et al. (2000) reported a 4.5-year-old boy who was admitted to the hospital at the age of 3.5 years with acute renal failure due to uric acid nephropathy. A streptococcal throat infection and fever were present at the same time and may have been precipitating or contributing factors. The precise nature of the DNA change was not described. The authors stated that the underlying HPRT mutation was unique in that the specific activity in HPRT and erythrocyte and fibroblast lysates was normal, but the rate of uptake of hypoxanthine into nucleotides of intact cultured fibroblasts was markedly reduced (23% of normal). Other metabolic features of the mutation were described as well. With allopurinol treatment, the patient had had no further problems and was developing normally at 5 years of age.
Srivastava et al. (2002) reported the case of a 12-year-old boy who presented with recurrent acute renal failure from hyperuricemia and had no phenotypic features of Lesch-Nyhan syndrome. Acute infectious mononucleosis may have triggered the acute renal failure, and treatment with allopurinol prevented further episodes. Unlike the cells from patients with Lesch-Nyhan syndrome, the in vitro cultures of this patient's T lymphocytes did not proliferate in the presence of purine analog 6-thioguanine.
Madeo et al. (2019) described the association between HPRT mutations and residual enzymatic activity in 76 French and Italian patients including 52 with LNS, 18 with the LNS neurologic variant (see 300322), and 6 with HRH. HPRT enzyme activity was measured in red blood cell lysates via a chromatographic assay using radiolabeled hypoxanthine. HPRT activity was significantly lower in LNS compared with attenuated variants and higher in HRH than in phenotypes with neurologic involvement. There was not a significant difference in residual enzyme activity between patients with LNS and the neurologic variant.
In 2 brothers with hyperuricemia and nephrolithiasis, Fujimori et al. (1988) identified a missense mutation in the HPRT gene (I132M; 308000.0001).
In a male with severe precocious gout and uric acid nephrolithiasis, Davidson et al. (1989) identified a missense mutation in the HPRT gene (D201G; 308000.0003).
In a patient with recurrent acute renal failure from hyperuricemia, Srivastava et al. (2002) identified a novel HPRT missense mutation (R48H; 308000.0059).
Andres, A., Praga, M., Ruilope, L. M., Martinez, J. M., Millet, V. G., Bello, I., Rodicio, J. L. Partial deficit of hypoxanthine guanine phosphoribosyl transferase presenting as acute renal failure. Nephron 46: 179-181, 1987. [PubMed: 3600927] [Full Text: https://doi.org/10.1159/000184337]
Davidson, B. L., Pashmforoush, M., Kelley, W. N., Palella, T. D. Human hypoxanthine-guanine phosphoribosyltransferase deficiency: the molecular defect in a patient with gout (HPRT-Ashville). J. Biol. Chem. 264: 520-525, 1989. [PubMed: 2909537]
Fujimori, S., Hidaka, Y., Davidson, B. L., Palella, T. D., Kelley, W. N. Identification of a single nucleotide change in a mutant gene for hypoxanthine-guanine phosphoribosyltransferase (HPRT-Ann Arbor). Hum. Genet. 79: 39-43, 1988. [PubMed: 2896620] [Full Text: https://doi.org/10.1007/BF00291707]
Kelley, W. N., Rosenbloom, F. M., Henderson, J. F., Seegmiller, J. E. A specific enzyme defect in gout associated with overproduction of uric acid. Proc. Nat. Acad. Sci. 57: 1735-1739, 1967. [PubMed: 4291947] [Full Text: https://doi.org/10.1073/pnas.57.6.1735]
Madeo, A., Di Rocco, M., Brassier, A., Bahi-Buisson, N., De Lonlay, P., Ceballos-Picot, I. Clinical, biochemical and genetic characteristics of a cohort of 101 French and Italian patients with HPRT deficiency. Molec. Genet. Metab. 127: 147-157, 2019. [PubMed: 31182398] [Full Text: https://doi.org/10.1016/j.ymgme.2019.06.001]
McDonald, J. A., Kelley, W. N. Lesch-Nyhan syndrome: altered kinetic properties of mutant enzyme. Science 171: 689-691, 1971. [PubMed: 4322125] [Full Text: https://doi.org/10.1126/science.171.3972.689]
Srivastava, T., O'Neill, J. P., Dasouki, M., Simckes, A. M. Childhood hyperuricemia and acute renal failure resulting from a missense mutation in the HPRT gene. Am. J. Med. Genet. 108: 219-222, 2002. [PubMed: 11891689] [Full Text: https://doi.org/10.1002/ajmg.10217]
Yu, T.-F., Balis, M. E., Krenitsky, T. A., Dancis, J., Silvers, D. N., Elion, G. B., Gutman, A. B. Rarity of X-linked partial hypoxanthine-guanine phosphoribosyltransferase deficiency in a large gouty population. Ann. Intern. Med. 76: 255-264, 1972. [PubMed: 5009592] [Full Text: https://doi.org/10.7326/0003-4819-76-2-255]
Zoref-Shani, E., Feinstein, S., Frishberg, Y., Bromberg, Y., Sperling, O. Kelley-Seegmiller syndrome due to a unique variant of hypoxanthine-guanine phosphoribosyltransferase: reduced affinity for 5-phosphoribosyl-1-pyrophosphate manifested only at low, physiological substrate concentrations. Biochim. Biophys. Acta 1500: 197-203, 2000. [PubMed: 10657589] [Full Text: https://doi.org/10.1016/s0925-4439(99)00103-9]