Lesch–Nyhan Syndrome

Abstract Lesch–Nyhan syndrome is a dramatic X‐linked disease caused by deficient activity of the purine‐salvage enzyme hypoxanthine–guanine phosphoribosyltransferase (HPRT), leading to hyperuricemia and all of its clinical consequences. These manifestations, which the disease shares with gout, include hematuria, renal calculi, renal failure resulting from urate deposition in the parenchyma of the kidney, acute very painful arthritis, and tophaceous deposits in the cartilage of joints and the ears. The disease also includes a neurologic syndrome in which dystonia and its involuntary movements are associated with spasticity, making most patients wheelchair bound. Behavioural manifestations, possibly the most memorable feature of the disease, include self‐injurious behaviour. This takes a spectrum of forms, the most drastic of which is biting which leads to loss of tissue. The activity of the enzyme is readily measured in red blood cells. In the classic syndrome the activity is zero. Key Concepts: Lesch–Nyhan disease was the first example of a stereotyped pattern of abnormal behaviour in which there was a fundamental molecular etiology, the absence of activity of an enzyme. The disease led to the development of the concept of behavioural phenotypes, and the coining of this phrase. The gene is located on the X chromosome, and its expression in disease is almost exclusively in males. Mutations in the gene represent the entire spectrum from missense and nonsense mutations to large deletions, and the rule in any family is for the mutation to be private. The discovery of allopurinol, which lowers uric acid concentrations by inhibiting xanthine oxidase, has changed the pattern of disease from one of death in early infancy to childhood; now there are adults with the disease. Successful treatment for neurologic and behavioural features of the disease has been elusive. The enzyme is active in every cell. This fact has permitted some control of the disease in a family by heterozygote detection and pre‐natal diagnosis. Heterozygote detection and pre‐natal diagnosis may be made by mutational analysis if mutation in the proband is known.