PRPP Synthetase Superactivity
PRPP synthetase superactivity (not a deficiency, but rather enzyme overactivity) is the enzymatic abnormality that most characteristically causes increased phosphoribosyl pyrophosphate (PRPP) levels. 1
Key Distinction: Overactivity vs. Deficiency
The question asks about enzymatic deficiency causing increased PRPP, but this represents a common conceptual pitfall. Increased PRPP levels result from PRPP synthetase superactivity (gain-of-function), not deficiency. 1 This is an important diagnostic distinction when evaluating patients with hyperuricemia and neurological symptoms.
Diagnostic Context and Testing Algorithm
When evaluating elevated uric acid levels, particularly in the context of autism spectrum disorders or unexplained hyperuricemia:
- First, measure serum and urine uric acid levels 1
- If elevated, proceed with testing for:
- If uric acid is low, consider a purine/pyrimidine panel (measuring uracil excretion, xanthine, hypoxanthine) 1
HGPRT Deficiency: The Alternative Cause of Hyperuricemia
While PRPP synthetase superactivity increases PRPP directly, HGPRT deficiency also leads to increased PRPP accumulation indirectly because HGPRT normally consumes PRPP in the purine salvage pathway. 2, 3
HGPRT Deficiency Clinical Spectrum:
- Complete deficiency causes Lesch-Nyhan syndrome with severe action dystonia, choreoathetosis, cognitive deficits, self-injurious behavior, and uric acid overproduction 2
- Partial deficiency (Kelley-Seegmiller syndrome) presents with variable neurological symptoms ranging from mild to severe, always with hyperuricemia 3
- All HGPRT-deficient patients demonstrate uric acid overproduction associated with lithiasis and gout 2
- X-linked recessive inheritance affects males primarily, with females as carriers 2
Diagnostic Approach for HGPRT Deficiency:
- Clinical findings: Hyperuricemia, hyperuricosuria, psychomotor delay 2
- Enzymatic testing: HGPRT activity determination in hemolysate, intact erythrocytes, or fibroblasts 2
- Molecular testing: Over 300 disease-associated mutations in the HPRT1 gene have been identified on Xq26 2, 4
Critical Clinical Pitfall
Do not confuse enzyme deficiency with enzyme superactivity. The question's phrasing suggests a deficiency causing increased PRPP, but increased PRPP results from PRPP synthetase overactivity. However, HGPRT deficiency can also lead to PRPP accumulation through impaired consumption in the salvage pathway. 1, 2
Management Considerations
- For uric acid overproduction: Allopurinol treatment with carefully adjusted doses to avoid xanthine lithiasis 2
- For neurological manifestations: Benzodiazepines and GABA inhibitors like baclofen for spasticity and dystonia 2
- Physical rehabilitation: Management of dysarthria, dysphagia, hand control devices, walking aids, and posture management 2