A prospective, multicenter international study of neurological manifestations of Lesch-Nyhan disease variants is reported from Emory University School of Medicine, Atlanta, GA. Of 46 patients (age range 3 to 65 years) from 34 families, 43 (93%) had neurological dysfunction. Classic cases with self-injurious behavior were excluded. Variant cases were male and had overproduction of uric acid and deficiency of the enzyme hypoxanthine-guanine phosphoribosyl-transferase or evidence for an HPRT gene mutation. Eight had gout, 6 had kidney problems, and 1 had a tophus. Delay in motor and speech development was common. Motor abnormalities in 42 (91%) ranged from subtle clumsiness to severely disabling generalized dystonia. Mild to moderate cognitive dysfunction was present in 31 (67%). Maladaptive behaviors included onychophagia in 6 patients, and impulsivity, OCD, aggression, OCD and anxiety in isolated cases. Together with 78 prior reports of 127 Lesch-Nyhan disease variants, a spectrum of clinical features includes patients with a full phenotype of classical L-N disease and patients with uric acid overproduction but no neurological or behavioral deficits. Between classical and asymptomatic variants are patients with varying degrees of motor, cognitive, or behavioral abnormalities. Of 47 previously reported cases of L-N variants, 18 (38%) had extrapyramidal features, 19 (40%) hyperreflexia and spasticity, 19 (40%) dysarthria, and 7 (15%) seizures. [1]

COMMENT. The diagnosis of classical Lesch-Nyhan disease is not difficult when a young child presents with self-injurious behavior, symptoms of hyperuricemia, and early-onset dystonia or clumsiness. In patients with attenuated variants of L-N disease, diagnosis should be suspected when a child has nephrolithiasis, gout, and motor or cognitive abnormalities. Serum uric acid may be normal or mildly elevated initially, and molecular testing for mutations of HPRT gene sometimes unavailable. A knowledge of the spectrum of neurological variants of L-N disease should lead to more prompt diagnosis, treatment, and carrier identification for family counseling.