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:

1. In male and female relatives: molecular genetic testing if a PRPS1 pathogenic variant has been identified in an affected family member;

2. 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.