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  • Updated 06.23.2022
  • Released 12.28.1993
  • Expires For CME 06.23.2025

Lesch-Nyhan disease

Introduction

Overview

This article reviews classic Lesch-Nyhan disease and less severe Lesch-Nyhan disease variants. These metabolic disorders result from mutations in the HPRT1 gene, which encodes for the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Lesch-Nyhan disease is an X-linked genetic disorder characterized by hyperuricemia, intellectual disability, dysarthric speech, early-onset hypotonia, later-onset dystonic movement disorder, and compulsive self-mutilation accompanied by an extended cognitive and behavioral phenotype.

Management of Lesch-Nyhan disease incorporates psychosocial support to the patient and caregivers, behavioral and pharmacological treatment, use of protective equipment, and dental, orthopedic, and nephrology management. Goals of treatment in Lesch-Nyhan disease include reduction of self-mutilating and aggressive behavior, prevention of renal failure and urologic complications related to hyperuricemia, control of dystonic movements, and orthopedic correction of hip subluxation and dislocation.

Key points

• Lesch-Nyhan disease is a metabolic disorder resulting from deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase that is involved in recycling the purines hypoxanthine and guanine.

• This X-linked genetic disorder is associated with hyperuricemia, intellectual disability, dysarthric speech, early hypotonia, dystonic movement disorder, and compulsive self-mutilation.

• Lesch-Nyhan disease is characterized by an extended behavioral, neurologic, and neurocognitive phenotype.

• Human studies and animal models of Lesch-Nyhan disease have documented dopaminergic dysfunction.

• Management of Lesch-Nyhan disease incorporates psychosocial support to the patient and caregivers, behavioral and pharmacological treatment, use of protective equipment, and dental, orthopedic, and nephrology management.

• Goals of treatment in Lesch-Nyhan disease include reduction of self-mutilating and aggressive behavior, prevention of renal failure and urologic complications related to hyperuricemia, control of dystonic movements, and orthopedic correction of hip subluxation and dislocation.

Historical note and terminology

Lesch-Nyhan disease was initially described in 1964 in two brothers by American cardiologist Michael Lesch (1939-2008) and his mentor, pediatrician and biochemical geneticist William Nyhan (b. 1928), both working at the Laboratory of General and Comparative Biochemistry at the NIH National Institute of Mental Health in Bethesda, Maryland (87; 102). The 4-year-old younger brother had been diagnosed with cerebral palsy and presented with hematuria. Both he and his 8-year-old brother had intellectual disability, a movement disorder with dystonia, renal stones, and self-biting.

In 1967, just 3 years after the clinical recognition of the disorder by Lesch and Nyhan, American rheumatologist and biochemical geneticist J(arvis) ("Jay") Edwin Seegmiller (1920-2006) and colleagues from the National Institutes of Health discovered the biochemical basis of Lesch-Nyhan syndrome, establishing it as a disease with a defined cause (130).

American rheumatologist and biochemical geneticist J Seegmiller (1920-2006) c.1966

J(arvis) ("Jay") Seegmiller is best known for his role in discovering the biochemical basis of Lesch-Nyhan syndrome, establishing it as a disease with a defined cause. (Source: National Institutes of Health. See: Anonymous. Drs...

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) was identified as the missing enzyme involved in this metabolic disorder.

Most patients with classical Lesch-Nyhan disease have low or undetectable levels of the HPRT, rarely more than 1%. The complete amino acid sequence for HPRT was described in 1982, and its three-dimensional structure was described using x-ray crystallography in 1994, along with the effects of single amino acid substitutions on the stability and activity (150; 37). Kinetic mechanisms of HPRT function were described in 1997 (153).

The gene was localized to the long arm of the X chromosome (q26-q27) in 1979, and the organization of the HPRT1 gene (approximately 44 kb; 9 exons) was described in 1986 (12; 82).

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