Lesch-Nyhan disease

Lesch-Nyhan disease (LND) is a rare X-linked inborn error of metabolism caused by a deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).

Characterized by hyperuricemia and a typical neurobehavioral phenotype, including a hyperkinetic movement disorder dominated by dystonia, attentional deficits, and behavioral disturbances with self-injury. Virtually all patients are male.

LND should be considered when delayed development is accompanied by a hyperkinetic movement disorder, including dystonia, particularly when routine brain MRI is normal. LND should be suspected if a delayed development is accompanied by self-injurious behavior or evidence of excessive production of uric acid.

Diagnosis is based on HPRT enzyme activity, preferably measured in live cells such as cultured fibroblasts, and on molecular genetic techniques demonstrating the gene mutation. Results might provide predictive clues about ultimate disease severity.

Currently, no established curative treatment is available. Supportive care includes muscle relaxants for the movement disorder, and physical restraints or teeth extraction to prevent self-injury.

LND is a rare X-linked inborn error of metabolism, caused by a mutation in the gene encoding the purine recycling enzyme HPRT.[1]Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med. 1964;36:561-570. http://www.ncbi.nlm.nih.gov/pubmed/14142409?tool=bestpractice.com [2]Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science. 1967;155:1682-1684. http://www.ncbi.nlm.nih.gov/pubmed/6020292?tool=bestpractice.com ​ The first description was in 1964, when two brothers originally diagnosed with cerebral palsy were later recognized as living with a previously undescribed inherited metabolic disease because of the familial occurrence and unusual clinical features.[1]Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med. 1964;36:561-570. http://www.ncbi.nlm.nih.gov/pubmed/14142409?tool=bestpractice.com HPRT deficiency causes overproduction of uric acid, which may lead to hyperuricemia, nephrolithiasis, gouty arthritis, and subcutaneous tophi.[3]Jinnah HA, Friedmann T. Lesch-Nyhan disease and its variants. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The metabolic and molecular bases of inherited disease. New York, NY: McGraw-Hill; 2001:2537-2570. In addition, patients exhibit a distinctive neurobehavioral phenotype, characterized by dystonia, attentional deficits, and behavioral disturbances including self-injury, presumably attributable to dysfunction of the basal ganglia dopamine system.[4]Visser JE, Bar PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev. 2000 Apr;32(2-3):449-75. http://www.ncbi.nlm.nih.gov/pubmed/10760551?tool=bestpractice.com Patients with a partial enzyme deficiency (Lesch-Nyhan variants [LNV]) display an incomplete phenotype: overproduction of uric acid with or without neurologic dysfunction, and no self-injury.[3]Jinnah HA, Friedmann T. Lesch-Nyhan disease and its variants. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The metabolic and molecular bases of inherited disease. New York, NY: McGraw-Hill; 2001:2537-2570.[5]Jinnah HA, Ceballos-Picot I, Torres RJ, et al; Lesch-Nyhan Disease International Study Group. Attenuated variants of Lesch-Nyhan disease. Brain. 2010 Mar;133(Pt 3):671-89. http://brain.oxfordjournals.org/content/133/3/671 http://www.ncbi.nlm.nih.gov/pubmed/20176575?tool=bestpractice.com