Severe phosphoribosylpyrophosphate synthetase superactivity (ORPHA:411543)
A severe form of phosphoribosylpyrophosphate (PRPP) synthetase superactivity, an X-linked disorder of purine metabolism, characterized by early onset hyperuricemia and hyperuricosuria, and clinically manifesting with urolithiasis, gout and neurodevelopmental anomalies consisting of variable combinations of sensorineural hearing loss, hypotonia, and ataxia.
Epidemiology
PRPP synthetase superactivity is a rare disorder with 30 families described in the literature. The severe form accounts for approximately 25% of cases. The disorder predominantly affects males.
Clinical description
The phenotype varies greatly among patients. The severe form manifests in infancy or early childhood (but may occur earlier) usually with uric acid crystalluria and urinary stones (kidney and/or bladder), followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. This form also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Axonal neuropathy with demyelination is also possible (reported in one family).
Etiology
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 PRPS1 gene (Xq22.3), encoding PRS-I, that lead to defective allosteric control of PRS1 isoform activity.
Diagnostic methods
Diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by either molecular genetic testing or a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes.
Differential diagnosis
Differential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor delay due to S-adenosylhomocysteine hydrolase deficiency.
Antenatal diagnosis
Prenatal genetic testing in male fetuses is possible where a mutation has previously been identified in a family member.
Genetic counseling
Severe PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance in males. A mother carrying the pathogenic mutation has a 50% chance of transmitting the mutation to any of her offspring, an affected father transmits the mutation only to his daughters. Heterozygous females are typically asymptomatic; however, symptomatic females have been reported, most likely due to X-inactivation. De novo  PRSP1 mutations have also been reported.
Management and treatment
Treatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A high daily fluid intake is warranted; and, as needed, potassium citrate to alkalinize the urine in order to avoid the formation of kidney stones. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. Regular audiometric and neurologic evaluations are also recommended.
Prognosis
The prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated. Of note, the interventions have no known beneficial effect on hearing loss or neurologic impairment.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Dr Arjan DE BROUWER