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). ...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 ...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
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 ...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)
Phosphoribosylpyrophosphate synthetase (PRS) superactivity, part of the spectrum of PRPS1-related disorders, is characterized by:...
DiagnosisClinical DiagnosisPhosphoribosylpyrophosphate synthetase (PRS) superactivity, part of the spectrum of PRPS1-related disorders, is characterized by:A juvenile/adult-onset form with:HyperuricemiaHyperuricosuriaGouty arthritisUric acid urolithiasisAn infantile-onset form that includes the findings of the juvenile/adult-onset form plus:Sensorineural hearing impairmentHypotoniaAtaxiaTestingUric acid measurements. See Table 1.Table 1. Serum Urate Concentration and 24-Hour Urinary Uric Acid Excretion in PRS SuperactivityView in own windowPhenotypeSerum Urate (mg/dL or µmol/L)Urinary Uric Acid (mg/24 hrs) 1, 2Infantile onsetIncreasedIncreasedJuvenile/adult onsetIncreasedIncreasedNormal341. Urinary uric acid concentration is not as helpful because urinary volumes differ markedly.2. Although the ratio of urinary uric acid to creatinine concentration may be helpful, this has not been rigorously tested in PRS overactivity. 3. Value given is the limit of urate solubility in serum.4. “Normal” values vary by age and size. Value given in Table 1 is for adults on a “standard” diet with no medications influencing serum urate levels. For other individuals and children, daily uric acid excretion in excess of approximately 12 mg/kg/24 hours could be considered abnormal.Phosphoribosylpyrophosphate synthetase (PRS; EC 2.7.6.1) enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes (see Table 2) [Losman et al 1984, Becker et al 1987, Becker et al 1992, Torres et al 1996]. Table 2. Phosphoribosylpyrophosphate Synthetase (PRS) Enzyme Activity and Nucleotide Levels in PRS SuperactivityView in own windowPhenotypePRS Enzyme ActivityFibroblast Nucleotide Levels 1FibroblastsLymphoblastsErythrocytesInfantile onsetHighHighUsually low 2HighJuvenile/adult onsetHighNormalHighHighBecker et al [1986]1. Adenylates (AMP, ADP, ATP) and guanylates (GMP, GDP, GTP)2. In the case of mutations of PRPS1 (usually in the infantile-onset type) that lead to defective allosteric regulation of the activity of the PRS1 isoform contribution to total PRS activity, enhanced enzyme affinity for Pi (especially at concentrations <2-4 mmol/L) and reduced inhibition of activity by ADP and GDP are observed in cultured fibroblasts and lymphoblasts. However, PRS1 enzyme activity in erythrocytes is usually reduced or deficient because of instability of the mutant enzyme in red blood cells. Molecular Genetic Testing Gene. PRPS1, encoding the enzyme phosphoribosylpyrophosphate synthetase 1 (ribose-phosphate pyrophosphokinase 1), is the only gene known to be associated with PRS overactivity. Clinical testingSequence analysis. Sequencing of the seven exons of the open reading frame of PRPS1 identified point mutations in seven of approximately 30 affected individuals: Five males with metabolic and neurodevelopmental abnormalities in infancy or early childhoodOne male with onset of metabolic, but not neurodevelopmental, features in the teen yearsOne woman with late-childhood-onset gout who was heterozygous for a PRPS1 mutationAll of the PRPS1 mutations resulted in defects in the allosteric regulation of PRS1 enzyme activity by nucleotides and Pi (see Table 2). In most individuals with juvenile/adult-onset PRS superactivity, no PRPS1 cDNA sequence variants were identified in either the coding or 5’ and 3’ non-coding regions. Table 3. Summary of Molecular Genetic Testing Used in PRS SuperactivityView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPRPS1Sequence analysisPoint mutations25% 2Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Direct sequencing of PRPS1 exons or PRPS1 cDNA provides a means for definitive confirmation of the mutation only in the case of PRS superactivity with mutation in PRPS1. No mutation has been identified in the PRPS1 DNA of the majority of affected individuals, who are largely in the juvenile- and adult-onset groups. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. In individuals with suggestive clinical findings, abnormal serum urate concentration, and abnormal daily urinary uric acid excretion (see Table 1) with: The juvenile/adult-onset type: The diagnosis is established by increased PRS enzyme activity at all Pi concentrations, normal nucleotide (ADP/GDP) inhibition of enzyme activity, normal Km for Pi activation, and increased PRS1 transcript (northern analysis) and PRS1 isoform (isoelectric focusing/western blotting). Molecular genetic testing by sequence analysis is not helpful in establishing the diagnosis. The infantile-onset type: The diagnosis is established by abnormal Pi activation of PRS enzyme activity with increased affinity for Pi and decreased nucleotide (ADP/GDP) inhibition of activity. Molecular genetic testing by sequence analysis is used to confirm the presence of a mutation in the PRPS1 coding region.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family. Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or (b) if an affected male is not available for testing, molecular genetic testing by sequence analysis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersThe spectrum of PRPS1-related disorders includes the three phenotypes PRS superactivity, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and Arts syndrome, previously thought to be distinct entities (see Table 4).Table 4. Major Clinical Findings in PRPS1-Related Disorders by PhenotypeView in own windowPhenotypeClinical FindingGouty Arthritis 1Peripheral NeuropathyIntellectual DisabilitySNHL 2OtherPRS super-activityInfantile onset+--++Hypotonia, ataxiaJuvenile/ adult onset+--One individual--CMTX5-+-Early onsetOptic neuropathyArts syndrome--+Profound, congenitalHypotonia, ataxia, optic atrophy, ↑ risk infection1. Associated with hyperuricemia, hyperuricosuria2. SNHL = sensorineural hearing lossCMTX5 is characterized by peripheral neuropathy, early-onset sensorineural hearing impairment, and progressive optic neuropathy starting between ages eight and 13 years [Rosenberg & Chutorian 1967, Kim et al 2007]. Progressive hypotonia, gait disturbances, and loss of deep-tendon reflexes with an onset between ages ten and 12 years have also been reported. Affected individuals have normal intellect. Carrier females do not have findings of CMTX5.Arts syndrome is characterized by intellectual disability, early-onset hypotonia, ataxia, delayed motor development, profound congenital sensorineural hearing impairment, and optic atrophy [de Brouwer et al 2007]. Susceptibility to infections, especially of the upper respiratory tract, often results in early death. Carrier females can show a single manifestation or milder manifestations (e.g., hearing impairment, ataxia, hypotonia, and/or hyperreflexia) than affected males.
PRS superactivity can be divided into a severe phenotype and a mild phenotype. ...
Natural History PRS superactivity can be divided into a severe phenotype and a mild phenotype. The severe phenotype is characterized by infantile- or early-childhood-onset hyperuricemia and hyperuricosuria. Uric acid crystalluria or a urinary stone is commonly the first metabolic clinical event and gouty arthritis is usually a later event if serum urate concentration is not controlled. Commonly, the clinical picture is dominated by events not directly ascribable to hyperuricemia or hyperuricosuria – usually variable combinations of sensorineural hearing loss, hypotonia, and ataxia [Becker et al 1988]. The milder phenotype is characterized by late-juvenile- or early-adult-onset gouty arthritis or uric acid urolithiasis with hyperuricemia and hyperuricosuria. Obvious neurologic findings are usually not present.Renal impairment can potentially result from uric acid crystal deposition in the renal collecting system or from urate crystal deposition in the renal interstitium.Kidney stones and acute renal failure as a result of obstructive uropathy from uric acid crystal deposition (stones or gravel) were described in the first family identified [Sperling et al 1972]; the renal failure resolved with treatment of the obstruction.Carrier females in families with the severe form of PRS superactivity can also show the metabolic and/or neurodevelopmental features of the disease [García-Pavia et al 2003].
No correlation between specific PRPS1 point mutations and the three phenotypes in the PRPS1-related disorders has been found....
Genotype-Phenotype CorrelationsNo correlation between specific PRPS1 point mutations and the three phenotypes in the PRPS1-related disorders has been found.
Purine and pyrimidine disorders. Disorders of purine and pyrimidine metabolism that overlap with PRPS1-related disorders are hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) deficiency (see also Lesch-Nyhan Syndrome) and S-adenosylhomocysteine hydrolase (AHCY) deficiency [Baric et al 2004]. ...
Differential DiagnosisPurine and pyrimidine disorders. Disorders of purine and pyrimidine metabolism that overlap with PRPS1-related disorders are hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) deficiency (see also Lesch-Nyhan Syndrome) and S-adenosylhomocysteine hydrolase (AHCY) deficiency [Baric et al 2004]. Table 5. Disorders of Purine and Pyrimidine Metabolism that Overlap with PRPS1-Related DisordersView in own windowClinical FindingPRS SuperactivityHPRT DeficiencyAHCY DeficiencyNeurologicIntellectual disability-±-Ataxia±--Hypotonia±±+Delayed motor development±++Loss of deep tendon reflexes--+Hearing impairment+--Uric acid overproductionGout++-Kidney stones++-Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).PRS superactivity, infantile onsetPRS superactivity, late-juvenile/early-adult onsetPRS superactivity, female carriers
To establish the extent of disease in an individual diagnosed with Phosphoribosylpyrophosphate synthetase (PRS) superactivity, the following evaluations are recommended....
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Phosphoribosylpyrophosphate synthetase (PRS) superactivity, the following evaluations are recommended.Juvenile/adult onset Serum uric acid concentration (if not already done)Measurement of daily uric acid excretion in the urine, which is particularly helpful in assessment of response to treatmentJoint examination for evidence of gout; generally, evaluation of joint integrity only, except during an acute flare of arthritis or in a case of chronic deformity or tophus formation following multiple attacksAssessment of renal function and renal structural integrity (e.g., renal ultrasound examination)Infantile onset. In addition to all evaluations listed under juvenile/adult onset:Neurologic evaluation for hypotonia, ataxia, presence/absence of tendon reflexesAudiometry for evidence of hearing loss, a critical differential pointTreatment of ManifestationsHyperuricemia and hyperuricosuria in individuals with PRS superactivity can be reduced by treatment with the following:Reduced intake of red meat, poultry, and shellfish [Choi et al 2004], avoidance of high-fructose corn syrup-containing foods and drinks, and increased low-fat dairy intake Allopurinol, a xanthine oxidase inhibitor, in whatever dose is needed to achieve serum urate concentrations lower than 6.0 mg/dL. Starting dose should be 100 mg (in adults) with titration every three to four weeks according to the serum urate concentration. Because of the uric acid overproduction and excessive uric acid excretion, allopurinol should be prescribed as soon as baseline data are obtained and the diagnosis is established. The newer urate-lowering xanthine oxidase inhibitor, febuxostat, has not been tested in patients with PRPP synthetase overactivity, but there is no reason a priori to doubt that it will be effective in the treatment of this disorder. Note: Excretion of more than 1.1 g uric acid per day in an adult is associated with a greater than 50% risk of kidney stones.High daily fluid intake (i.e., ≥2 L/day in the adult)Potassium citrate (usually administered 4x/day to alkalinize the urine) when urinary tract stones are present or uric acid gravel is in the urine [Becker 2008]Note: The interventions described only prevent/treat gout and the other metabolic complications of hyperuricemia; they have no known beneficial effect on hearing loss or neurodevelopmental impairment. Sensorineural hearing loss. See Deafness and Hereditary Hearing Loss Overview, Management.Ataxia. See Hereditary Ataxias, Management.Prevention of Secondary ComplicationsBy analogy to the case in HGPRT deficiency, another state of marked purine overproduction, xanthine oxidase inhibition with allopurinol may result in the formation of xanthine urinary tract stones. These radiolucent stones can be confused clinically with uric acid stones. Should residual symptoms of urolithiasis occur in PRS superactivity despite the achievement of goal serum urate concentrations, a stone should be isolated for analysis and/or urinary xanthine concentration should be measured. Management of this pharmacologically induced complication includes reduction in daily allopurinol dosing, with the possible need to accept serum urate concentrations higher than the usual goal range (<6.0 mg/dL).SurveillanceOnce a normal serum urate concentration is achieved and maintained, serum urate concentration should be monitored annually to assure that the targeted concentration is maintained. Under usual circumstances, renal functional consequences are avoided if serum urate concentration and urinary excretion of urate are normalized. Repeat audiometry as per treating audiologist/otolaryngologist is appropriate. Annual or more frequent neurologic evaluation as recommended by treating neurologist is appropriate. Agents/Circumstances to AvoidThe following should be avoided: Red meat, shellfish, beer, high-fructose corn syrup-enriched foods and drinks [Choi et al 2004] Dehydration If possible, urate-retaining medications: low-dose aspirin, thiazide diureticsEvaluation of Relatives at RiskIt is appropriate to screen at-risk male relatives with measurement of serum urate concentration and 24-hour urinary uric acid excretion. Note: (1) Because measuring 24-hour urine in an infant or young child is very difficult, measurement of uric acid to creatinine ratio in a spot urine sample can be helpful. (2) Sometimes the serum urate concentrations are not extremely high in children with PRS superactivity, probably as a result of high-level renal function; however, in all cases, the serum urate concentrations are abnormally high for age. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationDietary S-adenosylmethionine (SAM) supplementation could theoretically alleviate some of the symptoms of Arts syndrome (an allelic disorder) by providing an oral source purine nucleotide precursor that is not PRPP dependent. Furthermore, SAM is known to cross the blood-brain barrier. An adult with HPRT deficiency has been reported as benefiting neurologically from SAM administration without untoward side effects [Glick 2006]. An open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome is continuing (J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia). Oral SAM supplementation is presently set at 30 mg/kg/day. The boys appear to have had significant benefit from this therapy based on decreased number of hospitalizations, and stabilization of nocturnal BIPAP requirements, however slight deterioration in their vision has been noted. . Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Whether treatment with SAM supplementation would benefit individuals with allelic disorders (PRS superactivity, Charcot-Marie-Tooth neuropathy X type 5) remains to be investigated.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPRPS1Xq22.3Ribose-phosphate pyrophosphokinase 1IPN Mutations, PRPS1 PRPS1 @ LOVD PRPS1 homepage - Leiden Muscular Dystrophy pagesPRPS1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity (View All in OMIM) View in own window 300661PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY 311850PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1Normal allelic variants. PRPS1 has seven exons.Pathologic allelic variants. All known mutations are missense mutations that are distributed throughout the gene. Normal gene product. Ribose-phosphate pyrophosphokinase 1 (also known as phosphoribosylpyrophosphate synthetase 1) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis.Abnormal gene product. PRS superactivity is an inborn error of purine metabolism. All of the mutations identified to date in individuals with the PRS superactivity phenotype have resulted in defective allosteric regulation of PRS1 enzyme activity; however, this finding is biased by the fact that mutations were sought on the basis of metabolic and neurodevelopmental phenotypes.