Lesch-Nyhan Syndrome: Enzyme Deficiency and Pathophysiology
Direct Answer
This 2-year-old male has Lesch-Nyhan syndrome, caused by complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), which leads to purine overproduction because the salvage pathway cannot recycle hypoxanthine and guanine back to nucleotides, forcing cells to synthesize purines de novo at an accelerated rate. 1, 2
a. Enzyme Deficiency
Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is completely deficient in this patient. 1, 2
- HPRT normally catalyzes the conversion of hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP) in the purine salvage pathway 1
- Complete HPRT deficiency (< 0.05% of normal activity) is diagnostic of classic Lesch-Nyhan syndrome 2, 3
- The clinical triad of orange urate crystals in diapers, neurological dysfunction, and self-mutilating behavior is pathognomonic for complete HPRT deficiency 1, 2
b. Mechanism of Purine Overproduction
HPRT deficiency causes purine overproduction through loss of negative feedback regulation on the de novo synthesis pathway. 1
The Salvage Pathway Failure
- Normally, HPRT recycles free purine bases (hypoxanthine and guanine) back into usable nucleotides (IMP and GMP), providing an energy-efficient alternative to de novo synthesis 1
- When HPRT is absent, these salvaged purines cannot be converted to nucleotides and are instead oxidized to uric acid by xanthine oxidase 4, 1
- This creates a cellular "purine deficit" despite high uric acid levels, because the cell lacks the nucleotides it needs for DNA/RNA synthesis and cellular function 1
De Novo Pathway Acceleration
- The loss of IMP and GMP production from the salvage pathway removes critical negative feedback inhibition on phosphoribosyl pyrophosphate (PRPP) amidotransferase, the rate-limiting enzyme of de novo purine synthesis 1
- Without this feedback inhibition, PRPP amidotransferase activity increases dramatically, driving excessive de novo purine production 1
- The newly synthesized purines are eventually degraded to uric acid, compounding the hyperuricemia from failed salvage of hypoxanthine and guanine 1, 5
Quantitative Impact
- Hypoxanthine levels are elevated 8.4-9.0 standard deviations above normal mean in Lesch-Nyhan patients 5
- Xanthine levels are elevated 4-6 standard deviations above normal mean 5
- The combined elevation of these metabolites (n > 12.9 standard deviations) provides chemical confirmation of HPRT deficiency even in patients treated with allopurinol 5
Clinical Implications and Management
Diagnostic Confirmation
- Diagnosis requires demonstration of HPRT activity < 0.05% of normal in erythrocyte lysates or intact erythrocytes 2, 3
- Hyperuricemia (typically > 8 mg/dL) and hyperuricosuria with orange urate crystals are present from early infancy 1, 3
- Molecular analysis of the HPRT1 gene on Xq26 confirms diagnosis and enables carrier detection and prenatal diagnosis 1, 2
Treatment Approach
- Allopurinol is mandatory to prevent uric acid nephropathy and nephrolithiasis by inhibiting xanthine oxidase 4, 1
- Doses must be carefully titrated to avoid xanthine lithiasis, as xanthine crystalluria has been reported in Lesch-Nyhan patients 4
- Allopurinol reduces serum and urinary uric acid within 2-3 days but does not address neurological manifestations 4, 1
- Neurological symptoms (dystonia, spasticity) may respond to benzodiazepines and baclofen 1
- Self-injurious behavior requires physical restraints combined with behavioral and pharmaceutical interventions 1
Critical Pitfalls
- Do not delay allopurinol treatment while awaiting enzymatic confirmation, as renal damage from uric acid deposition begins in infancy 1
- Recognize that neurological dysfunction has no effective cure; physical rehabilitation and management of complications are the mainstay 1
- X-linked inheritance means female carriers are usually asymptomatic but require genetic counseling 1, 2
- De novo mutations occur at high rates, so absence of family history does not exclude diagnosis 5