Lesch-Nyhan syndrome is characterized by motor dysfunction that resembles cerebral palsy, cognitive and behavioral disturbances, and uric acid overproduction (hyperuricemia). The most common presenting features, hypotonia and developmental delay, are evident by age three to six months. Affected children are delayed in sitting and most never walk. Within the first few years, extrapyramidal involvement (e.g., dystonia, choreoathetosis, opisthotonos) and pyramidal involvement (e.g., spasticity, hyperreflexia, extensor plantar reflexes) become evident. Cognitive impairment and behavioral disturbances emerge between ages two and three years. Persistent self-injurious behavior (biting the fingers, hands, lips, and cheeks; banging the head or limbs) is a hallmark of the disease. Overproduction of uric acid may lead to deposition of uric acid crystals or calculi in the kidneys, ureters, or bladder. Gouty arthritis may occur later in the disease. Related disorders with less severe manifestations include hyperuricemia with neurologic dysfunction but no self-injurious behavior and hyperuricemia alone, sometimes with acute renal failure.
A urinary urate-to-creatinine ratio greater than 2.0, indicating uric acid overproduction (hyperuricemia), is a characteristic for children younger than age ten years who have Lesch-Nyhan syndrome. However, neither hyperuricuria nor hyperuricemia (serum uric acid concentration >8 mg/dL) is sensitive or specific enough for diagnosis. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme activity less than 1.5% of normal in cells from any tissue (e.g., blood, cultured fibroblasts, lymphoblasts) is diagnostic. Sequence analysis of HPRT1, the only gene known to be associated with Lesch-Nyhan syndrome, is available on a clinical basis.
Lesch-Nyhan syndrome is inherited in an X-linked manner. The father of an affected male will neither have the disease nor be a carrier of the mutant allele. The risk to sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the HPRT1 mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers. Thus, with each pregnancy, a carrier female has a 25% chance of having an affected male, a 25% chance of having a carrier female, and a 50% chance of having an unaffected male or female. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.