Phosphoribosylpyrophosphate synthetase superactivity (ORPHA:3222)
A rare X-linked disorder of purine metabolism associated with hyperuricemia and hyperuricosuria, and comprised of two forms: an early-onset severe form characterized by gout, urolithiasis, and neurodevelopmental anomalies and a mild late-onset form with no neurologic involvement.
Epidemiology
Phosphoribosylpyrophosphate (PRPP) synthetase superactivity is is a rare disorder with 30 families described in the literature to date. Males are predominantly affected.
Clinical description
Most individuals (approximately 75%) are affected by the milder form (mild PRPP synthetase superactivity), 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 (severe PRPP synthetase superactivity) 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.
Etiology
The disease is due to overactivity of ribose-phosphate pyrophosphokinase 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 the 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 PRS-I isoform activity. The exact molecular mechanism leading to the mild form is not yet well understood as no mutations have been found in PRPS1, but it seems to be linked to increased rates of PRPS1 transcription. Loss of function mutations in PRPS1 are linked to Charcot-Marie-Tooth X type 5, X-linked non-syndromic sensorineural deafness and Arts syndrome, together these diseases form part of a spectrum of PRPS1-related disorders.
Diagnostic methods
In both forms, diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes. Molecular genetic testing also confirms the diagnosis in the severe form.
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 are possible if the mutation has been previously identified in the family.
Genetic counseling
PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance. An affected mother has a 50% risk of transmitting the mutation to any of her offspring; an affected father transmits the mutation only to his daughters. De novo PRSP1 mutations have also been reported. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms.
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. For patients with the severe form, 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