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Other entities represented in this entry:
SNOMEDCT: 723454008; ORPHA: 3222, 411536, 411543; DO: 0111260;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq22.3 | Gout, PRPS-related | 300661 | X-linked recessive | 3 | PRPS1 | 311850 |
| Xq22.3 | Phosphoribosylpyrophosphate synthetase superactivity | 300661 | X-linked recessive | 3 | PRPS1 | 311850 |
A number sign (#) is used with this entry because the phenotype is caused by mutations in the gene encoding phosphoribosylpyrophosphate synthetase I (PRPS1; 311850) that result in increased enzyme activity.
X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) is an allelic disorder resulting from decreased enzyme activity. Affected individuals have neurologic symptoms, including sensorineural deafness. Another allelic disorder, Arts syndrome (301835), results from loss of PRPS1 activity and has a severe neurologic phenotype including mental retardation, early-onset hypotonia, and susceptibility to infections.
Phosphoribosylpyrophosphate synthetase I superactivity is an X-linked inborn error of metabolism in which increased enzyme activity is associated with hyperuricemia and gout. Some affected individuals have neurodevelopmental abnormalities, particularly sensorineural deafness (Becker et al., 1988; Roessler et al., 1993).
Although different kinetic defects affecting the PRPS1 enzyme have been identified in this disorder, the common pathway involves increased synthesis of phosphoribosylpyrophosphate (PRPP), which leads to increased uric acid and purine production (Becker, 2001).
Sperling et al. (1972, 1973) and Zoref et al. (1975, 1977) described a familial disorder characterized by early-adult onset of excessive purine production, gout, and uric acid urolithiasis associated with hyperuricemia and hyperuricosuria. The PRPS1 enzyme activity was described as 'superactive,' showing increased de novo synthesis of purine nucleotides. PRPS1 activity in red cells and cultured skin fibroblasts was resistant to feedback inhibition by guanosine diphosphate (GDP) and adenosine diphosphate (ADP). Fibroblast cultures were homogeneous for the mutant enzyme in affected males, whereas unaffected females showed mutant and normal activity. The pattern of inheritance was X-linked recessive.
Becker et al. (1980) provided follow-up studies of a family reported by Nyhan et al. (1969) in which a boy had hyperuricemia, mental retardation, and sensorineural deafness from infancy associated with PRPS1 superactivity. His affected mother had gout, uric acid urolithiasis, and significant hearing loss. Fibroblast studies of this patient and his mother indicated that the mutant enzyme had both regulatory and catalytic defects. The enzyme showed 4- to 5-fold greater than normal resistance to feedback inhibition and, in addition, increased maximal velocity of the enzyme reaction. The son was hemizygous, and his mother heterozygous, for the defect.
Simmonds et al. (1982) reported a 3-year-old boy with hypotonia, locomotor delay, and high frequency hearing loss associated with purine hyperactivity. The same disorder was probably present in 2 brothers who died in early childhood. The mother also showed hyperuricemia, purine overproduction, and sensorineural deafness from infancy. Severe depletion of red cell nicotinamide adenine dinucleotide (NAD) and GTP appeared to be associated with the neurologic abnormalities. Simmonds et al. (1982) referred to the report of Rosenberg et al. (1970) in which 5 family members had ataxia, deafness, hyperuricemia, and renal insufficiency. Serum urate levels were elevated in other members of the kindred who did not have renal insufficiency, indicating that the hyperuricemia was not secondary to renal disease. Red cell hypoxanthine-guanine phosphoribosyltransferase (HPRT1; 308000) levels were normal. The pedigree was consistent with X-linked inheritance with full expression in some females and incomplete expression in others. Riccardi (1974) studied the same family and concluded that X-linked dominant inheritance was unlikely because males seemed to be no more severely affected on the average than females.
Becker et al. (1988) reported a Spanish mother and son with PRPS1 superactivity. The 8-year-old boy had tophaceous gout, purine nucleotide and uric acid overproduction, and sensorineural deafness; his 27-year-old mother had gout. Fibroblast studies showed that the kinetic basis of superactivity in this family was resistance to purine nucleotide inhibition of enzyme activity. The boy was hemizygous, and his mother heterozygous, for the defect.
Christen et al. (1992) described a family with hyperuricemia and aberrant PRPS activity affecting the mother and 2 sons. Hypertonia and hyperuricemia were recognized in the mother at the age of 20 years; she later developed gouty arthritis. Her 2 sons were born prematurely by cesarean section. Gestational diabetes mellitus was diagnosed during the pregnancy with the first affected son, and both sons were diagnosed as having neonatal diabetes mellitus requiring insulin treatment through early childhood. Both boys showed growth retardation, mental and motor retardation with absent development of speech, muscular hypotonia (especially during the first year of life), cerebellar ataxia, and dysmetria, polyneuropathy with areflexia, and atrophy of the lower legs. All 3 had facial stigmata suggestive of a genetic syndrome, including triangular face with prominent forehead, epicanthus, hypotelorism, beaked nose, broad mouth, and hyperopia. Electroneurography in both boys demonstrated a progressive axonal neuropathy with demyelinization. Hearing was not impaired in any of the three. Crystals of urate could be seen in the diapers and on the tip of the penis in both boys, but both had normal renal function. Findings in fibroblasts and lymphoblasts of both boys suggested superactivity of PRPS due to resistance of the enzyme to nucleotide feedback.
Moran et al. (2012) described a patient with PRPS1 superactivity as well as features of Arts syndrome (301835), a developmental disorder also caused by mutations in the PRPS1 gene. Laboratory studies showed increased serum uric acid and increased urinary hypoxanthine consistent with PRPS1 superactivity, but he did not have gout. He had developmental delay, hypotonia, areflexia, motor neuropathy, sensorineural hearing loss, and a Chiari I malformation. In addition, he had recurrent infections and early death at age 27 months from infection, consistent with Arts syndrome. A maternal uncle with similar symptoms had died of pneumonia at age 2.
Becker et al. (1973) concluded that the PRPS mutation that led to gout in a family they studied was autosomal dominant, but in later studies (Yen et al., 1978) presented evidence for X-linkage: a daughter of an affected male had activity of the enzyme in fibroblasts intermediate between the normal and that of affected males. Furthermore, the affected mother showed 2 electrophoretically distinct bands of PRPS1 activity: 1 corresponding to the normal single band and 1 corresponding to the single band of affected males. However, erythrocytes and lymphocytes in the female showed increased synthetase activity of the same magnitude as that in affected males. This suggested nonrandom lyonization in progenitor cells or, more likely, selection against the cells with the wildtype X chromosome as the active one.
In a boy with hyperuricemia, sensorineural deafness, ataxia, and secondary renal insufficiency associated with PRPS1 superactivity reported by Becker et al. (1986), Roessler et al. (1991, 1993) identified mutation in the PRPS1 gene (311850.0001). Biochemical studies in fibroblasts were consistent with PRPS superactivity and purine nucleotide feedback-resistance.
In a son and mother with PRPS1 superactivity reported by Becker et al. (1980), Roessler et al. (1993) identified a mutation in the PRPS1 gene (311850.0002). Both had sensorineural hearing loss since infancy.
In a man with PRPS1 superactivity associated only with early-onset gout (Zoref et al., 1975), Becker et al. (1995) identified a hemizygous mutation in the PRPS1 gene (311850.0003).
In a patient with a complex phenotype comprising Arts syndrome and PRPS1 superactivity, Moran et al. (2012) detected a missense mutation in the transversion in exon 4 of the PRPS1 gene (V142L; 311850.0017).
Superactivity Due to Defective Allosteric Regulation of PRPS1
Becker et al. (1996) stated that defective allosteric regulation of PRPS1 activity by purine nucleotide inhibitors (such as ADP and GDP) and by the activator P(i) characterizes one kinetically defined class of superactive PRS that result from point mutations in the PRPS1 gene (Becker et al., 1995; Becker et al., 1996).
Catalytic Superactivity of PRPS1
Becker et al. (1973, 1973) reported 2 brothers with gout and excessive purine synthesis associated with increased intrinsic catalytic activity of the PRPS enzyme.
Becker et al. (1986) studied fibroblasts and red cells from 4 unrelated males with early-adult onset of hyperuricemia, gout, and uric acid overproduction. The kinetic basis of enzyme superactivity in all patients was determined to be increased maximal reaction velocity. Affinities for substrate activators and responsiveness to inhibitors were normal, and all had increased phosphoribosylpyrophosphate concentration and generation. Cultured fibroblasts of female relatives of 2 patients showed evidence of heterozygosity as measured by enzyme activities and rates of purine synthesis. Altered physical properties of the superactive enzymes suggested that several distinctive variants may be represented.
Becker et al. (1996) noted that in a second and more frequently encountered class of PRPS superactivity, regulation of enzyme activity by nucleotide inhibitors is normal, as are affinities for substrates and activators such as Mg(2+) and P(i). This so-called inherited 'catalytic' superactivity was unassociated with alteration in the translated sequences of either PRPS1 or PRPS2 cDNA, which is in contrast to PRPS superactivity associated with defective allosteric regulatory properties. Rather, catalytic overactivity of PRPS appeared to reflect increased intracellular concentrations of the normal PRPS1 isoform. Accumulating increases in levels of PRPS1 transcript with entirely normal sequence in cells from affected individuals suggested derangement of a pretranslational mechanism regulating the expression of PRPS1 in catalytic superactivity of PRPS.
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Becker, M. A., Losman, M. J., Wilson, J., Simmonds, H. A. Superactivity of human phosphoribosyl pyrophosphate synthetase due to altered regulation by nucleotide inhibitors and inorganic phosphate. Biochim. Biophys. Acta 882: 168-176, 1986. [PubMed: 2423135] [Full Text: https://doi.org/10.1016/0304-4165(86)90151-0]
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Becker, M. A., Puig, J. G., Mateos, F. A., Jimenez, M. L., Kim, M., Simmonds, H. A. Inherited superactivity of phosphoribosylpyrophosphate synthetase: association of uric acid overproduction and sensorineural deafness. Am. J. Med. 85: 383-390, 1988. [PubMed: 2843048] [Full Text: https://doi.org/10.1016/0002-9343(88)90591-8]
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Becker, M. A., Smith, P. R., Taylor, W., Mustafi, R., Switzer, R. L. The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity. J. Clin. Invest. 96: 2133-2141, 1995. [PubMed: 7593598] [Full Text: https://doi.org/10.1172/JCI118267]
Becker, M. A., Taylor, W., Smith, P. R., Ahmed, M. Overexpression of the normal phosphoribosylpyrophosphate synthetase 1 isoform underlies catalytic superactivity of human phosphoribosylpyrophosphate synthetase. J. Biol. Chem. 271: 19894-19899, 1996. [PubMed: 8702702] [Full Text: https://doi.org/10.1074/jbc.271.33.19894]
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Christen, H.-J., Hanefeld, F., Duley, J. A., Simmonds, H. A. Distinct neurological syndrome in two brothers with hyperuricaemia. (Letter) Lancet 340: 1167-1168, 1992. [PubMed: 1359249] [Full Text: https://doi.org/10.1016/0140-6736(92)93202-x]
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