Phosphoribosylpyrophosphate synthetase superactivity

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.

Orpha Number: 3222

Definition

Phosphoribosylpyrophosphate (PRPP) synthetase superactivity is an X-linked disorder of purine metabolism associated with hyperuricemia and hyperuricosuria, comprised of two forms: an early-onset severe form characterized by gout, urolithiasis, and neurodevelopmental anomalies (severe PRPP synthetase superactivity) and a mild late-onset form with no neurologic involvement (mild PRPP synthetase superactivity) (see these terms).

Epidemiology

PRPP synthetase superactivity is a rare disorder with less than 30 families described in the literature to date.

Clinical description

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.

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 PRSP1 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 PRSP1 , but it seems to be linked to increased rates of PRSP1 transcription.

Diagnostic methods

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

Differential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor retardation due to S-adenosylhomocysteine hydrolase (AHCY) deficiency (see these terms).

Antenatal diagnosis

Carrier testing for at-risk relatives and prenatal testing in male fetuses are possible if the mutation has been identified in the family.

Genetic counseling

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 offspring; an affected father transmits the mutation only to his daughters. 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 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.

Prognosis

The prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated.

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