Phosphoribosylpyrophosphate (PRPP) synthetase superactivity is an X-linked disorder of purine metabolism associated with hyperuricemia and hyperuricosuria, and comprising two forms: an early-onset severe form characterized by gout, urolithiasis, and neurodevelopmental anomalies, and a mild late-onset form with no neurologic involvement.
PRPP synthetase superactivity is a rare disorder with less than 30 families described in the literature.
PRPP synthetase superactivity affects mainly males. Most individuals (approximately 75%) are affected by the milder form, which manifests in late adolescence or early adulthood usually with uric acid crystalluria and (kidney and/or bladder) urinary stones, followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. The severe form usually starts from infancy or early childhood and shares the same clinical features with the mild form but also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms.
The disease is due to overactivity of PRPP synthetase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). In the severe form, PRS-I overactivity is due to gain-of-function point mutations in the open reading frame of the PRSP1 gene (Xq22.3) encoding PRS-I, that lead to defective allosteric control of PRS1 isoform activity. The exact molecular mechanism leading to the mild form is not yet well understood as no mutations have been found in PRSP1,but it seems to be linked to increased rates of PRSP1 transcription.
In both forms, diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes. Molecular genetic testing also confirms the diagnosis in the severe forms.
Differential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and S-adenosylhomocysteine hydrolase (AHCY) deficiency (see these terms).
Carrier testing for at-risk relatives and prenatal testing in male fetuses are possible if the mutation has been identified in the family.
PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance. An affected mother has a 50% chance of transmitting the disease to any of her offsprings, an affected father transmits the mutation only to his daughters. De novo PRSP1 mutations have also been reported.
Treatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. Alcalinisation of urine is recommended in order to avoid the formation of kidney stones. For patients with the severe form, regular audiometric and neurologic evaluations are also recommended.
The prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated.
Last update: April 2014