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Phosphoribosylpyrophosphate Synthetase Superactivity

, PhD, , PhD, and , MBBS, PhD.

Author Information

Initial Posting: ; Last Update: December 17, 2015.

Summary

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.

Diagnosis/testing.

Detection of high activity or lack of allosteric regulation of the PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis in individuals with both the severe early-onset phenotype and the milder late-juvenile/adult-onset phenotype. Identification of a hemizygous PRPS1 pathogenic variant on molecular genetic testing establishes the diagnosis only in individuals with the severe early-onset form, which comprises approximately one fourth of the group of individuals with PRS superactivity.

Management.

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 such as allopurinol and a low-purine, low-fructose diet. (Note: These interventions have no known beneficial effect on hearing loss or neurologic impairment.)

Surveillance: Monthly measurement of 24-hour urinary uric acid excretion or a spot urinary urate/creatinine ratio helps in assessing the response to treatment; once a normal serum urate concentration is achieved, serum urate concentration should be monitored at a minimum annually to assure that target urate concentration is maintained; a 24-hour urine should be monitored at a minimum annually for urate and xanthine particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L); 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 pathogenic variant, the chance of transmitting the PRPS1 pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and have a range of clinical manifestations. Males pass the pathogenic variant to all of their daughters and none of their sons. Heterozygote (carrier) testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in the family.

Diagnosis

Suggestive Findings

The mild phenotype of PRS superactivity should be suspected in a juvenile or adult male proband with the following:

  • Gouty arthritis (Note: Absence of gout does not exclude PRS superactivity)
  • Significant hyperuricemia (see Table 1)
  • Significantly elevated daily urinary uric acid excretion (see Table 1)
  • Uric acid urolithiasis

The severe phenotype of PRS superactivity should be suspected in a male infant or young child with the following clinical features in addition to the above findings:

  • Intellectual disability
  • Sensorineural hearing impairment
  • Hypotonia
  • Ataxia

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
1.

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

2.

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.

3.

Male and female adult serum urate ranges differ.

4.

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

Establishing the Diagnosis

Male proband. The mild phenotype is established in a juvenile or adult by identifying increased PRS-I enzyme activity at all inorganic phosphate (Pi) concentrations, normal dinucleotide (ADP/GDP) inhibition of enzyme activity, normal Km for Pi activation, and increased PRPS1 transcript (e.g., by northern analysis or quantitative real-time PCR) and PRS-I isoform (isoelectric focusing/western blotting).

PRS-I enzyme activity causing the mild phenotype 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].

Note: Molecular genetic testing by PRPS1 sequence analysis is not helpful in establishing the diagnosis in individuals with juvenile/adult onset as pathogenic variants within the PRPS1 coding sequence leading to elevated PRPS1 mRNA levels have not been identified as yet.

The severe phenotype is established in an infant or young child by identifying abnormal Pi activation of PRS-I enzyme activity in fibroblasts or lymphoblasts, but not erythrocytes (see Table 2), with increased affinity for Pi and decreased dinucleotide (ADP/GDP) inhibition of activity.

Identification of a hemizygous PRPS1 pathogenic variant on molecular genetic testing confirms the diagnosis (see Table 3).

Female proband. The diagnosis of PRS superactivity is usually established in a female proband with gout, sensorineural hearing impairment, and the identification of a heterozygous pathogenic variant in PRPS1 by molecular genetic testing (see Table 3).

Table 2.

Phosphoribosylpyrophosphate Synthetase (PRS) Enzyme Activity and Nucleotide Levels in PRS Superactivity

PhenotypePRS-I Enzyme ActivityFibroblast Nucleotide Levels 1
FibroblastsLymphoblastsErythrocytes
Infantile onsetHighHighUsually low 2High
Juvenile/adult onsetHighNormalHighHigh
1.

Adenylates (AMP, ADP, ATP) and guanylates (GMP, GDP, GTP)

2.

PRPS1 pathogenic variants (usually in the infantile-onset type) that lead to defective allosteric regulation of the activity of the PRS-I 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, PRS-I enzyme activity in erythrocytes is usually reduced or deficient because of instability of the mutated enzyme in red blood cells.

Molecular genetic testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of PRPS1.
  • A multi-gene panel that includes PRPS1 and other genes of interest (see Differential Diagnosis) may also be considered.
    Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • More comprehensive genomic testing – when available – including whole-exome sequencing (WES) and whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of PRS superactivity. For issues to consider in interpretation of genomic test results, click here.

Table 3.

Molecular Genetic Testing Used in PRS Superactivity

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
PRPS1Sequence analysis 3, 47 out of 30 5
Gene-targeted deletion/duplication analysis 6None reported
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis

5.

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 pathogenic variant. All of the respective PRPS1 pathogenic variants resulted in defects in the allosteric regulation of PRS-I enzyme activity by nucleotides and Pi (see Table 2) No PRPS1 pathogenic variant has been identified in the majority of affected individuals, who are largely in the juvenile- and adult-onset groups.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

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.

Heterozygous females in families with the severe form of PRS superactivity can also show the metabolic and/or neurodevelopmental features of the disease [García-Pavía et al 2003].

Genotype-Phenotype Correlations

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

Pathogenic variants that lead to DFNX1 either disturb local stability of PRS-I or moderately affect interactions in the trimer interface.

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

Penetrance

Penetrance is complete in hemizygous males.

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, single-nucleotide variants (SNVs) 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 SNVs. However, the distinction has not gained wide recognition.

Prevalence

No prevalence has been estimated. To date, 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 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 Disorders

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

Management

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. Consultation with a medical geneticist and/or genetic counselor
  • 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 an individual with 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. Febuxostat should also be prescribed conservatively, because of a high risk for xanthinuria causing renal lithiasis.
    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 4x/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 or febuxostat 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 or febuxostat dosing, with the possible need to accept serum urate concentrations higher than the usual goal range (<6.0 mg/dL; 360 μmol/L).

Surveillance

Monthly measurement of 24-hour 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.

A 24-hour urine should also be monitored at a minimum annually for urate and xanthine concentrations particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L); 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 the 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 apparently asymptomatic older and younger at-risk relatives (regardless of gender) of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

Evaluations include:

  • Molecular genetic testing if the pathogenic variant in the family is known;
  • If the pathogenic variant in the family is not known, 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 collection of 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 higher renal clearance of urate, however the urine urate excretion is abnormally high for age in all individuals.

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].

For an open-label clinical trial of SAM in two Australian brothers (from ages 14 and 13 in 2010) with Arts syndrome [Christodoulou et al, unpublished data] (approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia), oral SAM supplementation was set at 30 mg/kg/day. The boys appeared 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 was noted. Eventually, they both died of respiratory failure at the ages of 19 and 18 years in association with a severe lower respiratory tract infection.

Mildly affected heterozygous 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.

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

  • The father of an affected male will neither have PRS superactivity nor be hemizygous for the PRPS1 pathogenic variant. However, because the prevalence of gout in men is high, the father may have gout unrelated to PRS superactivity.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier).
  • If a male is the only affected family member (i.e., a simplex case), several possibilities regarding his mother's genetic status need to be considered:
    • He has a de novo PRPS1 pathogenic variant, in which case his mother is not a heterozygote. The frequency of de novo pathogenic variants is not known.
    • His mother has a de novo PRPS1 pathogenic variant either as (a) a "germline pathogenic variant" (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 PRPS1 pathogenic variant that she inherited from her mother or her (affected) father.

Parents of a female proband

  • A female proband may have inherited the PRPS1 pathogenic variant from either her mother or her father or the pathogenic variant may be de novo.
  • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PRPS1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, it is possible (though not likely) that the mother or father may have germline mosaicism.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband has a PRPS1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and have a range of possible clinical manifestations.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PRPS1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

  • If the mother of the proband has a PRPS1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and have a range of possible clinical manifestations.
  • If the father of the proband has a PRPS1 pathogenic variant, he will transmit it to all his daughters and none of his sons.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PRPS1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a male proband. Affected males transmit the PRPS1 pathogenic variant to:

  • All of their daughters who will be heterozygotes and have a range of possible clinical manifestations;
  • None of their sons.

Offspring of a female proband. Women with a PRPS1 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child:

  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the pathogenic variant will be heterozygotes and have a range of possible clinical manifestations.

Other family members. If a parent of the proband also has a pathogenic variant, his or her female family members may be at risk of being heterozygous (and having a range of possible clinical manifestations) and his or her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: Females who are heterozygous for a PRPS1 pathogenic variant have a range of possible clinical manifestations.

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 genetic 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 heterozygotes, or are at risk of being heterozygotes.

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 PRPS1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

This approach to prenatal diagnosis is most applicable to the severe infantile-onset form of PRPP synthetase (PRS) superactivity, in which PRPS1 pathogenic variants 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for some families in which the PRPS1 pathogenic variant has been identified.

Resources

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
    Email: sis@aaidd.org
  • 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
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Medline Plus
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • 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)
    Email: cdcinfo@cdc.gov
  • Purine Metabolic Patients’ Association (PUMPA)
    United Kingdom
    Phone: 44 (0)20 8725 5898
    Email: info@pumpa.org.uk
  • Purine Research Society
    5424 Beech Avenue
    Bethesda MD 20814-1730
    Phone: 301-530-0354
    Fax: 301-564-9597
    Email: PurineResearchSociety@verizon.net

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)

300661PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY
311850PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1

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

Pathogenic allelic variants. All known pathogenic variants are missense variants that are distributed throughout the gene.

Normal gene product. Phosphoribosylpyrophosphate synthetase 1 (also known as ribose-phosphate pyrophosphokinase 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 pathogenic variants identified to date in individuals with the PRS superactivity phenotype have resulted in defective allosteric regulation of PRS-I enzyme activity; however, this finding is biased by the fact that pathogenic variants were sought on the basis of metabolic and neurodevelopmental phenotypes.

References

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. Chap 106. New York, NY: McGraw-Hill; 2008:2513-35.
  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-Pavía 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. 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]
  13. 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]
  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 online. Accessed 12-11-15.

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

  • 17 December 2015 (me) Comprehensive update posted live
  • 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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