Clinical Guidance

No genotype-phenotype correlations have been identified.

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Superactivity"

Diagnostic Criteria

No consensus clinical diagnostic criteria for phosphoribosylpyrophosphate synthetase (PRS) superactivity have been published. 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 Enzyme Analysis The diagnosis of the mild PRS superactivity phenotype is established in a male or female proband with by detection of high activity or lack of allosteric regulation of the PRS-I enzyme (PRS-I enzyme assay). PRS-I enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [, , , ]. 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 blot analysis or quantitative real-time PCR) and PRS-I isoform (isoelectric focusing/ western blotting) establish the diagnosis. See . Table 1. Phosphoribosylpyrophosphate Synthetase (PRS) Enzyme Activity and Nucleotide Levels in PRS Superactivity

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Superactivity"

Differential Diagnosis

Disorders of purine and pyrimidine metabolism to consider in the differential diagnosis of phosphoribosylpyrophosphate synthetase (PRS) superactivity are: • Hypoxanthine-guanine phosphoribosyltransferase deficiency, an X-linked disorder caused by pathogenic variants in HPRT1 (see HPRT1 Disorders); • Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, an autosomal recessive disorder caused by pathogenic variants in AHCY (OMIM 613752). Table 3. Disorders of Purine and Pyrimidine Metabolism that Overlap with Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity

Management Guidelines

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:

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Superactivity"

Clinical Guidance

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

• Dehydration

• If possible, urate-retaining medications: low-dose aspirin, thiazide diuretics

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Superactivity"

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.

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Superactivity"

Surveillance Guidelines

All Individuals

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-to-creatinine ratio can be informative if accessibility to 24-hour urine 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. 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).

Individuals with the Severe PRS Superactivity Phenotype

Audiometry should be repeated as deemed appropriate by the treating audiologist/otolaryngologist. Neurologic evaluation should be performed annually or more frequently as recommended by the treating neurologist. Monitor developmental progress and educational needs at each visit.

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Superactivity"