Clinical Diagnosis

Phosphoribosylpyrophosphate synthetase (PRS) superactivity, part of the spectrum of PRPS1-related disorders, is characterized by:

• A juvenile/adult-onset form with:
  • Hyperuricemia
  • Hyperuricosuria
  • Gouty arthritis
  • Uric acid urolithiasis
• An infantile-onset form that includes the findings of the juvenile/adult-onset form plus:
  • Sensorineural hearing impairment
  • Hypotonia
  • Ataxia

Testing

Uric acid measurements. See Table 1.

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]. Such testing is available on a research basis only.

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 testing

• Sequence 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 childhood
  • One male with onset of metabolic, but not neurodevelopmental, features in the teen years
  • One woman with late-childhood-onset gout who was heterozygous for a PRPS1 mutation

All 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 Superactivity

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PRPS1	Sequence analysis	Point mutations	25% 2	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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). Such testing is available on a research basis only.
  • 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. Such testing is available on a research basis only.
  • 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The 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).

CMTX5 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.

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].

Genotype-Phenotype Correlations

No correlation between specific PRPS1 point mutations and the three phenotypes in the PRPS1-related disorders has been found.

Penetrance

Penetrance is complete.

Nomenclature

“PRPP synthetase (PRS) superactivity” is the name originally applied to the overall disorder. With the increasing recognition of two varieties of defects – that is, point mutations in PRPS1 and accelerated transcription of the normal PRPS1 (with an enzyme of normal kinetic characteristics) – it has been suggested that the term PRS “overactivity” become the overall name and that “superactivity” refer only to the phenotype associated with PRPS1 point mutations. However, the distinction has not gained wide recognition.

Prevalence

No prevalence has been estimated. Fewer than 30 individuals have been described with PRS superactivity worldwide [Becker 2008]

Evaluations 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 treatment
• Joint 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 attacks
• Assessment 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 reflexes
• Audiometry for evidence of hearing loss, a critical differential point

Treatment of Manifestations

Hyperuricemia 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 Complications

By 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).

Surveillance

Once 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 Avoid

The 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 diuretics

Testing of Relatives at Risk

It 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 Investigation

Dietary 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Phosphoribosylpyrophosphate synthetase (PRS) superactivity is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• In a family with more than one affected individual, the mother of an affected male is likely to be an obligate carrier.
  • A mother who is a carrier may have a de novo gene mutation or she may have inherited the disease-causing mutation either from her mother or from her father.
• The father of an affected male will have neither PRS superactivity nor the mutation. However, because the prevalence of gout in men is high, the father may have gout unrelated to PRS superactivity.
• When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation in PRPS1, in which case his mother is not a carrier. The frequency of de novo mutations is not known.
  • His mother has a de novo disease-causing mutation in PRPS1, either as (a) a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or as (b) "germline mosaicism" (i.e., present in some of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Parents of a female proband

• If the proband is a female and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to both of her parents to determine risks to family members.
• If the proband's father is asymptomatic, it is possible, but not likely, that he has the mutation in some cells in his body (somatic or germline mosaicism). If her father is asymptomatic and does not have somatic or germline mosaicism for the altered gene, the possible genetic explanations for the origin of the proband's gene mutation are the same as for a male proband with a negative family history.

Sibs of the proband

• The risk to the sibs of a proband depends on the genetic status of the parents.
  • If the mother has a disease-causing mutation, the chance of transmitting the PRPS1 mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and may or may not be affected.
  • If the father of a female proband is affected, all female sibs will inherit the mutation and may or may not be affected. None of the male sibs will inherit the mutation.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population.
  • If the disease-causing mutation cannot be detected in the DNA of either parent of the proband, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a male proband. Males pass the disease-causing mutation to all of their daughters and none of their sons.

Offspring of a female proband. Females with a PRPS1 gene mutation have a 50% chance of transmitting the gene to each child; sons who inherit the gene will be affected; daughters have a range of possible phenotypic expression.

Other family members of the proband. If a parent of the proband also has a disease-causing mutation, his or her female family members may be at risk of being carriers (asymptomatic or symptomatic) and his or her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Carrier Detection

Carrier testing is possible if the mutation has been identified in the family.

Related Genetic Counseling Issues

See Management, Testing Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified before prenatal testing can be performed. Thus, this approach to prenatal diagnosis is most applicable to the infantile-onset form of PRPP synthetase overactivity, in which mutations in PRPS1 are identifiable. In nearly all instances of juvenile/adult onset of this disorder, however, the sequence of the PRPS1 coding region and adjacent DNA is normal and the basis of increased rates of PRPS1 transcription is unknown. In instances in which a mutation in PRPS1 has been identified in the family, fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci U S A. 2004;101:4234–9. [PMC free article: PMC384724] [PubMed: 15024124]
2. Becker MA, Kim M, Husain K, Kang T. Regulation of purine nucleotide synthesis in human B lymphoblasts with both hypoxanthine-guanine phosphoribosyltransferase and phosphoribosylpyrophosphate synthetase superactivity. J Biol Chem. 1992;267:4317–21. [PubMed: 1311306]
3. Becker MA, Losman MJ, Kim M. Mechanisms of accelerated purine nucleotide synthesis in human fibroblasts with superactive phosphoribosylpyrophosphate synthetases. J Biol Chem. 1987;262:5596–602. [PubMed: 3032938]
4. Becker MA, Losman MJ, Wilson J, Simmonds HA. Superactivity of human phosphoribosyl pyrophosphate synthetase due to altered regulation by nucleotide inhibitors and inorganic phosphate. Biochim Biophys Acta. 1986;882:168–76. [PubMed: 2423135]
5. Becker MA, Puig JG, Mateos FA, Jimenez ML, Kim M, Simmonds HA. Inherited superactivity of phosphoribosylpyrophosphate synthetase: association of uric acid overproduction and sensorineural deafness. Am J Med. 1988;85:383–90. [PubMed: 2843048]
6. Becker MA. Hyperuricemia and gout. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio AB, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 106. New York: McGraw-Hill. 2008. Available at www​.ommbid.com. Accessed 10-29-10.
7. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004;350:1093–103. [PubMed: 15014182]
8. de Brouwer AP, Williams KL, Duley JA, van Kuilenburg AB, Nabuurs SB, Egmont-Petersen M, Lugtenberg D, Zoetekouw L, Banning MJ, Roeffen M, Hamel BC, Weaving L, Ouvrier RA, Donald JA, Wevers RA, Christodoulou J, van Bokhoven H. Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet. 2007;81:507–18. [PMC free article: PMC1950830] [PubMed: 17701896]
9. García-Pavia P, Torres RJ, Rivero M, Ahmed M, García-Puig J, Becker MA. Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman. Arthritis Rheum. 2003;48:2036–41. [PubMed: 12847698]
10. Glick N. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration. J Inherit Metab Dis. 2006;29:687. [PubMed: 16906475]
11. Kim HJ, Sohn KM, Shy ME, Krajewski KM, Hwang M, Park JH, Jang SY, Won HH, Choi BO, Hong SH, Kim BJ, Suh YL, Ki CS, Lee SY, Kim SH, Kim JW. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5). Am J Hum Genet. 2007;81:552–8. [PMC free article: PMC1950833] [PubMed: 17701900]
12. Losman MJ, Hecker S, Woo S, Becker MA. Diagnostic evaluation of phosphoribosylpyrophosphate synthetase activities in hemolysates. J Lab Clin Med. 1984;103:932–43. [PubMed: 6327865]
13. Rosenberg RN, Chutorian A. Familial opticoacoustic nerve degeneration and polyneuropathy. Neurology. 1967;17:827–32. [PubMed: 6069085]
14. Sperling O, Boer P, Persky-Brosh S, Kanarek E, De VA. Altered kinetic property of erythrocyte phosphoribosylpsyrophosphate synthetase in excessive purine production. Rev Eur Etud Clin Biol. 1972;17:703–6. [PubMed: 4346548]
15. Torres RJ, Mateos FA, Puig JG, Becker MA. Determination of phosphoribosylpyrophosphate synthetase activity in human cells by a non-isotopic, one step method. Clin Chim Acta. 1996;245:105–12. [PubMed: 8646809]

Suggested Reading

1. Becker MA. Phosphoribosylpyrophosphate synthetase superactivity. Orphanet. 2005. Available at www​.orpha.net. Accessed 10-29-10.

Revision History

• 11 January 2011 (cd) Revision: additions to therapies under investigation
• 2 November 2010 (me) Comprehensive update posted live
• 23 September 2008 (me) Review posted live
• 17 July 2008 (mb) Initial submission