Mild Phosphoribosylpyrophosphate Synthetase Superactivity

A mild form of phosphoribosylpyrophosphate (PRPP) synthetase superactivity, an X-linked disorder of purine metabolism, characterized by adolescent or early adult-onset hyperuricemia and hyperuricosuria, leading to urolithiasis and gout.

Epidemiology

PRPP synthetase superactivity is a rare disorder with 30 families described in the literature. The mild form accounts for approximately 75% of cases. The disorder predominantly affects males.

Clinical description

Mild PRPP synthetase superactivity typically manifests in late adolescence or early adulthood, but may manifest earlier, 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 is not associated with any neurodevelopmental anomalies.

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). The exact molecular mechanism leading to the mild form is not yet well understood, but it seems to be linked to increased rates of transcription of the gene PRSP1 (Xq22.3) encoding PRS-I .

Diagnostic methods

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.

Differential diagnosis

Differential diagnosis includes other causes urinary stones and gout. PRENATAL DIAGNOSIS (IF RELEVANT) Prenatal genetic testing in male fetuses may be possible if the mutation has been previously identified in the family.

Genetic counseling

Although no genetic mutation has been identified in this mild form, the pattern of inheritance is thought to be X-linked with complete penetrance in males. Females are not typically affected, but some females may show a mild clinical presentation.

Management and treatment

Hyperuricemia and hyperuricosuria are treated with: allopurinol or febuxostat to reduce uric acid formation and thus serum urate and urinary uric acid. A high daily fluid intake is recommended; and, as needed, potassium citrate to alkalinize the urine. Dietary recommendations include emphasis on low-fat dairy and complex carbohydrate-containing foods.

Prognosis

Severe gout can lead to renal impairment, if not properly treated.