Lesch–Nyhan Disease

Abstract Lesch–Nyhan disease (LND) is an X‐linked, inherited neurodevelopmental disease caused by a mutation in the gene encoding the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT). Virtual absence of HPRT is associated with hyperuricemia and specific neurobehavioural features: a hyperkinetic movement disorder dominated by dystonia, cognitive impairment with attentional and executive deficits, and behavioural disturbances including self‐injurious behaviour. Partial HPRT deficiencies result in incomplete phenotypes characterised by hyperuricemia with or without neurological dysfunction, but without self‐injury. HPRT deficiency leads to a deficiency of the neurotransmitter dopamine, and the subsequent dysfunction of the basal ganglia is thought to play an important role in the pathogenesis of the neurobehavioural phenotype. Administering allopurinol reduces the risk of hyperuricemia‐associated urological and articular complications, but there is currently no effective treatment for the neurobehavioural features of LND. Self‐injurious behaviour is managed by restraints and soft padding of the environment, and sometimes neuroleptics, anxiolytics or sedatives. Key Concepts: Lesch–Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT). LND is characterised by developmental delay, hyperuricemia, dystonia, attentional and executive deficits and behavioural disturbances including self‐injurious behaviour. The severity of the clinical phenotype in LND depends on the amount of residual HPRT enzyme activity. Dysfunction of the basal ganglia dopamine systems are thought to play an important role in the pathogenesis of the neurobehavioural phenotype. LND patients are not globally retarded, but rather have impairments in specific cognitive domains, including attentiveness and mental flexibility. Compulsive self‐injurious behaviour is considered a hallmark of the disease, and emerges usually within the first few years of life. HPRT enzyme activity testing or HPRT gene mutation analysis confirms the diagnosis. As effective treatment for LND is currently lacking, prevention through carrier testing, genetic counselling and prenatal diagnosis is of utmost importance.