Clinical characteristics.

Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria. The mild phenotype (~75% of affected males) with onset in the second or third decade of life is typically limited to these biochemical findings, whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia. In the mild phenotype, 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.

In male probands with the mild phenotype, detection of high activity or lack of allosteric regulation of the PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis. Molecular genetic testing of PRPS1 fails to detect a hemizygous pathogenic variant.

In male probands with the severe phenotype, molecular genetic testing establishes the diagnosis by identification of a hemizygous PRPS1 pathogenic variant in males and a heterozygous PRPS1 pathogenic variant in females.

In symptomatic female probands, PRS-I enzyme assay and/or PRPS1 molecular genetic testing establishes the diagnosis.

Management.

Treatment of manifestations: In all individuals, hyperuricemia and hyperuricosuria can be reduced by treatment 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.

In individuals with the severe phenotype, DD/ID, sensorineural hearing loss, hypotonia, and ataxia are managed per standard care.

Surveillance: All individuals: monthly measurement of 24-hour urinary uric acid excretion or a spot urinary urate-to-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 least annually for urate and xanthine particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L).

In the severe phenotype: monitor development / educational needs, neurologic manifestations, and hearing.

Agents/circumstances to minimize or avoid: In all individuals: 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, and if possible, urate-retaining medications (e.g., low-dose aspirin, thiazide diuretics).

Evaluation of relatives at risk: It is appropriate to screen apparently asymptomatic older and younger at-risk relatives of an individual with PRS superactivity in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures for hyperuricemia and hyperuricosuria. Evaluations include:

• In male and female relatives: molecular genetic testing if a PRPS1 pathogenic variant has been identified in an affected family member;
• In male relatives at risk: measurement of serum urate concentration and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio. Note: Biochemical testing is unlikely to be informative in asymptomatic females.

Genetic counseling.

PRS superactivity caused by a pathogenic variant in PRPS1 is inherited in an X-linked manner. Females who are heterozygous for a PRPS1 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be severely affected; females who inherit the pathogenic variant will be heterozygous and may be asymptomatic or have a range of features. Males with a PRPS1 pathogenic variant transmit the pathogenic variant to all of their daughters and none of their sons. If a PRPS1 pathogenic variant has been identified in the proband, heterozygote testing for at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

PRS superactivity caused by elevated PRPS1 mRNA levels is also inherited in an X-linked manner; however, because the underlying genetic alteration has not been characterized, the mode of inheritance cannot be confirmed with certainty.

Suggestive Findings

Phosphoribosylpyrophosphate synthetase (PRS) superactivity should be suspected in male and female probands with the following clinical and laboratory findings and family history.

The mild (onset in 2nd or 3rd decade of life) PRS superactivity phenotype should be suspected in a male or female proband with the following findings:

• Gouty arthritis
  Note: Absence of gout does not exclude consideration of PRS superactivity.
• Significant hyperuricemia and significantly elevated daily urinary uric acid excretion
  • The ratio of urinary urate 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" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
• Uric acid urolithiasis

The severe (onset in 1st decade of life) PRS superactivity phenotype should be suspected in a male or female proband with the above findings and the following additional clinical features:

• Intellectual disability
• Sensorineural hearing impairment
• Hypotonia
• Ataxia

Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Clinical Description

The two phosphoribosylpyrophosphate synthetase (PRS) superactivity phenotypes are mild (onset in 2nd or 3rd decade of life) and severe (onset in 1st decade of life).

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

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, 33 individuals with PRS superactivity have been described worldwide.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a male or female diagnosed with phosphoribosylpyrophosphate synthetase (PRS) superactivity, the following evaluations are recommended.

Mild (onset in 2nd or 3rd decade of life) PRS superactivity phenotype

• Serum urate concentration
• Joint examination for evidence of gout – generally, evaluation of joint integrity only, except during an acute flare of arthritis or in an individual with chronic deformity or tophus formation following multiple attacks
• Assessment of kidney function and structural integrity (e.g., kidney ultrasound examination)

Severe (onset in 1st decade of life) PRS superactivity phenotype. In addition to evaluations listed previously for the mild phenotype:

• Neurologic evaluation for hypotonia, ataxia, presence/absence of tendon reflexes
• Audiometry for evidence of hearing loss
• Developmental assessment, including motor, adaptive, cognitive, & speech-language evaluation
• Evaluation for early intervention / special education

All individuals. Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PRS superactivity in order to facilitate medical and personal decision making

Treatment of Manifestations ‒ All PRS Superactivity

Hyperuricemia and hyperuricosuria can be reduced by treatment with the following:

• Dietary changes:
  • Reduced intake of red and organ meats, poultry, and shellfish [Choi et al 2004], oily fish (e.g., anchovies, sardines), and beer
  • Avoidance of high-fructose corn syrup-containing foods and drinks
  • 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 Gout and renal lithiasis below.
• 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 an 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.

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

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.

Treatment of Manifestations ‒ Severe PRS Superactivity Phenotype

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 Ataxia Overview, Management).

Surveillance

Agents/Circumstances to Avoid

The following should be avoided in all individuals:

• 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 of an individual with PRS superactivity in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures for hyperuricemia and hyperuricosuria.

Evaluations include:

• In male and female relatives at risk for the severe phenotype: molecular genetic testing if a PRPS1 pathogenic variant has been identified in an affected family member;
• In male relatives at risk for the mild phenotype: measurement of serum urate concentration, and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio. Biochemical testing is unlikely to be informative in asymptomatic females.
  Note: (1) Because collection of 24-hour urine in an infant or young child is very difficult, measurement of urinary urate-to-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 in individuals with the severe PRS superactivity phenotype 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. This is an experimental drug that is as yet unproven.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Phosphoribosylpyrophosphate synthetase (PRS) superactivity caused by a pathogenic variant in PRPS1 is inherited in an X-linked manner.

PRS superactivity caused by elevated PRPS1 mRNA levels is also inherited in an X-linked manner; however, because the underlying genetic alteration has not been characterized, the mode of inheritance cannot be confirmed with certainty.

Risk to Family Members of a Proband with a PRPS1 Pathogenic Variant

Parents of a male proband

• The father of an affected male will not have PRS superactivity nor will he be hemizygous for the PRPS1 pathogenic variant; therefore, he does not require further evaluation/testing. (Note: 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. Note: If a woman has more than one affected child and no other affected relatives and if the familial PRPS1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo PRPS1 pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism. The frequency of de novo PRPS1 pathogenic variants is not known.
• Molecular genetic testing of the mother is recommended to allow reliable recurrence risk assessment and to determine her need for clinical management (see Surveillance).

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 severely affected.
  • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [García-Pavía et al 2003, Zikánová et al 2018] (see Clinical Description, Heterozygous Females).
• If the proband represents a simplex case and 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.

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 help to determine if the pathogenic variant was inherited.

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% (see Sibs of a male proband).
• 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 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 maternal or paternal germline mosaicism.

Offspring of a proband

• Affected males transmit the PRPS1 pathogenic variant to:
  • All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description, Heterozygous Females);
  • None of their sons.
• Women with a PRPS1 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child:
  • Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description, Heterozygous Females).
  • Males who inherit the pathogenic variant will be affected.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PRPS1 pathogenic variant, the parent's family members may be at risk.

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the PRPS1 pathogenic variant in the proband.

Of note, biochemical testing is unlikely to be informative in asymptomatic females.

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 and discussion of the availability of prenatal/preimplantation genetic 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 and/or are at risk of having PRS superactivity.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If a PRPS1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for PRS superactivity are possible. This approach to prenatal diagnosis is most applicable to the severe (onset in first decade of life) PRS superactivity phenotype, in which PRPS1 pathogenic variants are identifiable.

Note: The identification of a PRPS1 pathogenic variant in a male fetus predicts a phenotype consistent with severe PRS superactivity; the identification of a PRPS1 pathogenic variant in a female fetus cannot be used to reliably predict the phenotype because the manifestations in heterozygous females are variable.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PRS superactivity is an inborn error of purine metabolism. 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 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.

Mechanism of disease causation. Gain of function. Because all of the PRPS1 pathogenic variants identified to date in individuals with the PRS superactivity phenotype have resulted in defective allosteric regulation of PRS-I enzyme activity, this finding is biased by the fact that pathogenic variants were sought on the basis of metabolic and neurodevelopmental phenotypes.

PRPS1-specific laboratory technical considerations. Analysis of PRS-1 enzyme activity can be used to:

• Establish the diagnosis in individuals with the mild PRS superactivity phenotype;
• Evaluate novel PRPS1 variants of uncertain significance in individuals with the severe PRS superactivity phenotype by identifying abnormal Pi activation of PRS-I enzyme activity in fibroblasts or lymphoblasts, but not erythrocytes (see Table 1). The variant PRS-I enzyme has an increased affinity for inorganic phosphate (Pi) and decreased dinucleotide (ADP/GDP) inhibition of activity.

Analysis of PRS-1 enzyme activity is available at:

Department of Clinical Chemistry
Amsterdam University Medical Center
Amsterdam, the Netherlands
Phone: +31(0)20-5665393
Email: gmz_dna@amc.uva.nl

Acknowledgments

The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to Dr John Christodoulou is generously supported by the Royal Children's Hospital Foundation.

Author History

Michael A Becker, MD; University of Chicago Pritzker School of Medicine (2008-2013)
John Christodoulou, MBBS, PhD (2013-present)
Arjan PM de Brouwer, PhD (2013-present)
John A Duley, PhD; University of Queensland (2013-2022)

Revision History

• 17 February 2022 (bp) Comprehensive update posted live
• 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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