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Phosphoribosylpyrophosphate Synthetase Superactivity

Synonyms: PRPS1 Superactivity, PRS Overactivity, PRS Superactivity

, PhD, , PhD, and , MB BS, PhD.

Author Information
, PhD
Department of Human Genetics
Radboud University Nijmegen Medical Center
Nijmegen, The Netherlands
, PhD
The University of Queenland and
Mater Research
Brisbane, Australia
, MB BS, PhD
Disciplines of Paediatrics and Child Health & Genetic Medicine
University of Sydney
Western Sydney Genetics Program
Children’s Hospital at Westmead
Sydney, Australia

Initial Posting: ; Last Update: August 8, 2013.


Clinical characteristics.

Phosphoribosylpyrophosphate synthetase (PRS) superactivity is characterized by hyperuricemia and hyperuricosuria and is divided into a severe phenotype with infantile or early-childhood onset and a milder phenotype with late-juvenile or early-adult onset. Variable combinations of sensorineural hearing loss, hypotonia, and ataxia observed in the severe type are not usually present in the mild type. In the mild type, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled.


Detection of high activity or lack of allosteric regulation of the PRS enzyme (PRS enzyme assay) establishes the diagnosis. PRPS1, encoding ribose-phosphate pyrophosphokinase 1 (phosphoribosylpyrophosphate synthetase 1 [PRS1]), is the only gene in which mutations are known to cause PRS superactivity. PRPS1 sequence analysis identifies point mutations in individuals with the severe early-onset form, which comprises approximately 25% of the group of individuals with PRS superactivity.


Treatment of manifestations: Hyperuricemia and hyperuricosuria are treated with: allopurinol or febuxostat to reduce uric acid formation and thus serum urate and urinary uric acid; high daily fluid intake; and, as needed, potassium citrate to alkalinize the urine. Dietary recommendations include emphasis on low-fat dairy and complex carbohydrate-containing foods and avoidance of the foods and medications discussed below. Sensorineural hearing loss and ataxia are managed in the routine manner.

Prevention of primary manifestations: Hyperuricemia and hyperuricosuria can be prevented with a xanthine oxidase inhibitor and a low-purine, low-fructose diet. (Note: These interventions have no known beneficial effect on hearing loss or neurologic impairment.)

Surveillance: Daily measurement of uric acid secretion or a spot urinary urate/creatinine ratio helps in assessing the response to treatment; once serum urate concentration is achieved, serum urate concentration should be monitored at a minimum annually to assure the target urate concentration is maintained; repeat audiometry as indicated; routine neurologic evaluations as indicated.

Agents/circumstances to minimize or avoid: High-purine meats (i.e., red and organ meats), shellfish, oily fish (e.g., anchovies, sardines); beer; high-fructose corn syrup-containing beverages and foods; dehydration; if possible, urate-retaining medications (e.g., low-dose aspirin, thiazide diuretics).

Evaluation of relatives at risk: Screen at-risk relatives (regardless of gender) with measurement of serum urate concentration; 24-hour urinary uric acid excretion or spot urine uric acid to creatinine ratio; and an audiology evaluation.

Genetic counseling.

PRS superactivity is inherited in an X-linked manner. If the mother has a disease-causing mutation, the chance of transmitting the PRPS1 mutation in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and may or may not be affected. Males pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the mutation has been identified in the family.


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 (Note: Absence of gout does not exclude PRS superactivity.)
    • Uric acid urolithiasis
  • An infantile-onset form that includes the findings of the juvenile/adult-onset form plus:
    • Intellectual disability
    • Sensorineural hearing impairment
    • Hypotonia
    • Ataxia


Uric acid measurements. See Table 1.

Table 1.

Serum Urate Concentration and 24-Hour Urinary Uric Acid Excretion in PRS Superactivity

PhenotypeSerum Urate
(mg/dL or µmol/L) 1
Urinary Uric Acid
(mg/24 hrs) 2
Infantile onsetIncreasedSignificantly elevated
Juvenile/adult onsetIncreasedSignificantly elevated
Normal adult male >12y3.5-7.2 mg/dL or 210-430 µmol/L 3250-750 mg or 1.5-4.5 mmol per 24 hours; 4
200-500 mmol urate/mol creatinine
Normal adult female2.6-6.0 mg/dL or 150-360 µmol/LSame as adult male
Normal child ≤12y2.0-5.5 mg/dL or 120-330 µmol/L300-1400 mmol urate/mol creatinine
Normal infant <2y2.0-5.5 mg/dL or 120-330 µmol/L300-1800 mmol urate/mol creatinine

Serum and urine urate ranges are divided into child and adult. Recommended values here are for one specialist referral center; age and urate cutoffs vary locally.


The ratio of urinary uric acid to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.


Male and female adult serum urate ranges differ.


“Normal” values vary by age and weight. Values given in table are for a “standard” diet with no medications influencing serum urate levels.

Phosphoribosylpyrophosphate synthetase (PRS; EC 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 Superactivity

PhenotypePRS Enzyme ActivityFibroblast Nucleotide Levels 1
Infantile onsetHighHighUsually low 2High
Juvenile/adult onsetHighNormalHighHigh

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 inorganic phosphate (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 in which mutations are known to cause PRS superactivity.

Clinical testing

Table 3.

Summary of Molecular Genetic Testing Used in PRS Superactivity

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
PRPS1Sequence analysis 4Point mutations7 out of 30 5, 6
Deletion/duplication analysis 7UnknownUnknown; none reported 8

See Molecular Genetics for information on allelic variants.


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


Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


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 respective PRPS1 mutations resulted in defects in the allosteric regulation of PRS1 enzyme activity by nucleotides and Pi (see Table 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 in either the coding or 5’ and 3’ non-coding regions has been identified in the PRPS1 DNA of the majority of affected individuals, who are largely in the juvenile- and adult-onset groups.


Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exonic or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


No deletions or duplications involving PRPS1 as causative of PRPS1-related disorders, including phosphoribosylpyrophosphate synthetase (PRS) superactivity, have been reported.

Testing Strategy

To confirm/establish the diagnosis in a proband. In individuals with suggestive clinical findings, significantly elevated serum urate concentration, and significantly elevated 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 inorganic phosphate (Pi) concentrations, normal dinucleotide (ADP/GDP) inhibition of enzyme activity, normal Km for Pi activation, and increased PRS1 transcript (e.g., by northern analysis or quantitative real-time PCR) and PRS1 isoform (isoelectric focusing/western blotting).
    • Molecular genetic testing by PRPS1 sequence analysis is not helpful in establishing the diagnosis of this subtype as mutations within the PRPS coding sequence have not been identified as yet.
  • The infantile-onset type:
    • The diagnosis is established by abnormal Pi activation of PRS enzyme activity with increased affinity for Pi and decreased dinucleotide (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 features 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 for the severe infantile-onset form require prior identification of the disease-causing mutation in the family.

Clinical Characteristics

Clinical Description

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, intellectual disability, 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

Mutations that result in PRS superactivity disturb either one or both allosteric sites that are involved in the inhibition of PRS I enzyme activity.

Mutations that lead to DFN2 either disturb local stability of PRS I or moderately affect interactions in the trimer interface.

Computer-assisted molecular modeling has shown that mutations causing Arts syndrome and CMTX5 disturb the ATP binding site of PRS-I.


Penetrance is complete.


“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.


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

Differential Diagnosis

Purine and pyrimidine disorders. Disorders of purine and pyrimidine metabolism that overlap with PRPS1-related disorders are hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 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 Disorders

Clinical FindingPRS SuperactivityHPRT DeficiencyAHCY Deficiency
NeurologicIntellectual disability+±
Delayed motor development±++
Loss of deep tendon reflexes+
Hearing impairment+
Uric acid overproductionGout++
Kidney stones++


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with phosphoribosylpyrophosphate synthetase (PRS) superactivity, the following evaluations are recommended:

  • All individuals. Medical genetics consultation
  • Juvenile/adult onset
    • Serum uric acid concentration
    • 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 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 and organ meats, poultry, and shellfish [Choi et al 2004], oily fish (e.g. anchovies, sardines), beer, avoidance of high-fructose corn syrup-containing foods and drinks, and increased low-fat dairy intake
  • Allopurinol, a xanthine oxidase inhibitor, prescribed in doses with the ultimate aim of achieving serum urate concentrations lower than 6.0 mg/dL (360 μmol/L). The starting dose should be 100 mg once a day (in adults) with titration every three to four weeks according to the serum urate concentration. However, because of the uric acid overproduction and excessive uric acid excretion, allopurinol should be prescribed conservatively, as there is a high risk for xanthinuria and xanthine renal lithiasis – see Prevention of Secondary Complications.
  • Febuxostat, a newer urate-lowering xanthine oxidase inhibitor. Febuxostat has not been tested in individuals with PRS superactivity, but there is no reason a priori to doubt that it will be effective in the treatment of this disorder.
    Note: Excretion of >1.1 g uric acid per day in an adult is associated with a greater than 50% risk for kidney stones.
  • High daily fluid intake (i.e., ≥2 L/day in the adult)
  • Potassium citrate (usually administered 4 times/day to alkalinize the urine) when urate urinary tract stones are present or uric acid gravel is in the urine [Becker 2008]. Xanthinuria does not respond to urinary alkalinization.

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 is managed in the usual manner (see Deafness and Hereditary Hearing Loss Overview, Management).

Ataxia is managed in the usual manner (see Hereditary Ataxias, Management).

Prevention of Primary Manifestations

Gout and renal lithiasis caused by chronically elevated serum and urine uric acid, the result of purine overproduction, can be reduced by a xanthine oxidase inhibitor.

Some neurologic attributes of the severe form of the disease may be preventable by early treatment with S-adenosylmethionine (SAM), although this is experimental (see Therapies Under Investigation).

Prevention of Secondary Complications

By analogy to individuals with Lesch-Nyhan syndrome, who also have 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. If 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; 360 μmol/L).


Measurement of 24 h uric acid excretion in the urine is particularly helpful in the assessment of the response to treatment. Alternatively, a spot urinary urate/creatinine ratio can be informative if accessibility to samples is restricted.

Once a normal serum urate concentration is achieved and maintained, serum urate concentration should be monitored at a minimum annually to assure that the targeted concentration is maintained.

Urine should also be monitored at a minimum annually for xanthine concentrations (plasma xanthine is cleared efficiently and does not accumulate).

Audiometry should be repeated as deemed appropriate by treating audiologist/otolaryngologist.

Neurologic evaluation should be performed annually or more frequently as recommended by treating neurologist.

Note: Under usual circumstances, renal functional consequences are avoided if serum urate concentration and urinary excretion of urate are normalized and urinary xanthine does not routinely exceed its solubility (~1 mmol/L).

Agents/Circumstances to Avoid

The following should be avoided:

  • Red and organ meats, shellfish, or oily fish (e.g. anchovies, sardines) in excess; beer, high-fructose corn syrup-enriched foods and drinks [Choi et al 2004]
  • Dehydration
  • If possible, urate-retaining medications: low-dose aspirin, thiazide diuretics

Evaluation of Relatives at Risk

It is appropriate to screen at-risk relatives (regardless of gender) with measurement of serum urate concentration; 24-hour urinary uric acid excretion or spot urine uric acid/creatinine ratio; and an audiology evaluation. Note: (1) Because measuring 24-hour urine in an infant or young child is very difficult, measurement of uric acid/creatinine ratio in a spot urine sample may be helpful. (2) Sometimes the serum urate concentrations are not extremely elevated in children with PRS superactivity, probably as a result of high-level renal function; however, in all cases, the urine urate excretion is 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 may theoretically alleviate some of the neurologic symptoms of severe PRS superactivity by providing an oral source of purine nucleotide precursor that is not PRPP dependent. Furthermore, SAM is known to cross the blood-brain barrier. Although PRS superactivity exhibits high purine nucleotides (adenylates/guanylates) in some cells, these are low in red blood cells, which rely on purine salvage metabolism, and are believed to be low in the brain, which also relies on purine salvage metabolism.

An adult with Lesch-Nyhan syndrome 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 for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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.
  • 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:

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.

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, Evaluation of Relatives at Risk for information on evaluating 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing. This approach to prenatal diagnosis is most applicable to the severe infantile-onset form of PRPP synthetase (PRS) superactivity, 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 some families in which the disease-causing mutation has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
  • Medline Plus
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)

Molecular Genetics

Information 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 Superactivity: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Phosphoribosylpyrophosphate Synthetase Superactivity (View All in OMIM)


Gene structure. PRPS1 has seven exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. All known pathogenic variants 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. PRPS1 encodes a protein of 318 amino acid residues; only one protein isoform has been described.

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.


Literature Cited

  1. Arts WF, Loonen MC, Sengers RC, Slooff JL. X-linked ataxia, weakness, deafness, and loss of vision in early childhood with a fatal course. Ann Neurol. 1993;33:535–9. [PubMed: 8498830]
  2. 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]
  3. 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. Chap 106. New York, NY: McGraw-Hill; 2008:2513-35.
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. Glick N. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration. J Inherit Metab Dis. 2006;29:687. [PubMed: 16906475]
  12. 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]
  13. Liu X, Han D, Li J, Han B, Ouyang X, Cheng J, Li X, Jin Z, Wang Y, Bitner-Glindzicz M, Kong X, Xu H, Kantardzhieva A, Eavey RD, Seidman CE, Seidman JG, Du LL, Chen ZY, Dai P, Teng M, Yan D, Yuan H. Loss-of-function mutations in the PRPS1 gene cause nonsyndromic X-linked sensorineural deafness, DFN2. Am J Hum Genet. 2010;86:65–71. [PMC free article: PMC2801751] [PubMed: 20021999]
  14. 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]
  15. Rosenberg RN, Chutorian A. Familial opticoacoustic nerve degeneration and polyneuropathy. Neurology. 1967;17:827–32. [PubMed: 6069085]
  16. 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]
  17. 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 online. Accessed 12-10-14.

Chapter Notes

Author History

Michael A Becker, MD; University of Chicago Pritzker School of Medicine (2008-2013)
John Christodoulou, MB BS, PhD (2013-present)
Arjan PM de Brouwer, PhD (2013-present)
John A Duley, PhD (2013-present)

Revision History

  • 8 August 2013 (me) Comprehensive update posted live
  • 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
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Bookshelf ID: NBK1973PMID: 20301734


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