pediatrics
Purine Salvage Disorders
Lesch Nyhan syndrome
This is a rare, X-Linked Recessive disorder caused by deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT); degree of deficiency (and hence manifestations) vary with the specific mutation. HPRT deficiency results in failure of the salvage pathway for hypoxanthine and guanine. These purines are instead degraded to uric acid. Additionally, a decrease in inositol monophosphate and guanosyl monophosphate leads to an increase in conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) to 5-phosphoribosylamine, which further exacerbates uric acid overproduction. Hyperuricemia predisposes to gout and its complications. Patients also have a number of cognitive and behavioral dysfunctions, etiology of which is unclear; they do not seem related to uric acid. The disease usually manifests between 3 months and 12 months of age with the appearance of orange sandy precipitate (xanthine) in the urine; it progresses to central nervous system involvement with intellectual disability, spastic cerebral palsy, involuntary movements, and self-mutilating behavior (particularly biting). Later, chronic hyperuricemia causes symptoms of gout (eg, urolithiasis, nephropathy, gouty arthritis, tophi). Diagnosis of Lesch-Nyhan syndrome is suggested by the combination of dystonia, intellectual disability, and self-mutilation. Serum uric acid levels are usually elevated, but confirmation by DNA analysis is done. Central nervous system dysfunction has no known treatment; management is supportive. Self-mutilation may require physical restraint, dental extraction, and sometimes drug therapy; a variety of drugs has been used. Hyperuricemia is treated with a low-purine diet (eg, avoiding organ meats, beans, sardines) andallopurinol, a xanthine oxidase inhibitor (the last enzyme in the purine catabolic pathway).Allopurinolprevents conversion of accumulated hypoxanthine to uric acid; because hypoxanthine is highly soluble, it is excreted. 