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  • Updated 01.02.2020
  • Released 12.28.1993
  • Expires For CME 01.02.2023

Lesch-Nyhan disease

Introduction

This article includes discussion of Lesch-Nyhan disease, Lesch-Nyhan syndrome, HGPRT deficiency, HPRT deficiency, and hypoxanthine-guanine phosphoribosyltransferase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

In this article, the author reviews classic Lesch-Nyhan disease and more mildly affected Lesch-Nyhan disease variants. These metabolic disorder presentations result from mutations in the HPRT1 gene, which encodes for the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). Lesch-Nyhan disease is an X-linked genetic disorder characterized by hyperuricemia, intellectual disability, early-onset hypotonia with later onset of a predominantly dystonic movement disorder, dysarthric speech, and compulsive self-injury with self-mutilation accompanied by an extended cognitive and behavioral phenotype.

Studies in an Hprt1-deficient mutant mouse model and PET imaging studies have documented dopaminergic dysfunction with basal ganglia involvement. Management of hyperuricemia with allopurinol, dental management, orthopedic management, and use of protective equipment, along with behavioral interventions, is mandatory. Pharmacological treatment targets stabilization of mood and anxiety management. S-adenosylmethionine (SAMe), a physiological intermediate in methylation and transsulfuration, may have beneficial effects in selected patients who can tolerate the drug. Deep brain stimulation has been demonstrated in several case reports and series to reduce self-injury and aggression, and in some to modify dystonia.

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, early hypotonia and dystonic movement disorder, dysarthric speech, and compulsive self-injury with self-mutilation.

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

• Studies in an HPRT1-deficient mutant mouse model and PET imaging studies have documented dopaminergic dysfunction.

• Management of hyperuricemia with allopurinol, dental management, orthopedic management, and use of protective equipment, along with behavioral interventions, is mandatory.

Historical note and terminology

Lesch-Nyhan disease was initially described in 1964 in 2 brothers, 4 and 8 years of age (89). The younger brother had been diagnosed with cerebral palsy and presented with hematuria. Both he and his brother had intellectual disability, movement disorder with dystonia, renal stones, and self-biting. Subsequently, hypoxanthine-guanine phosphoribosyltransferase (HGprt) was identified as the missing enzyme involved in this metabolic disorder (136). The majority of patients with classical Lesch-Nyhan disease have low or undetectable levels of the hypoxanthine-guanine phosphoribosyltransferase enzyme, rarely more than 1%. Becker and associates localized the gene to the long arm of the X chromosome (q26-q27) (10). The complete amino acid sequence for hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) gene was described by Wilson and associates, and the organization of the HPRT1 gene (approximately 44 kb; 9 exons) was described by Kim and associates (157; 84).

Eads and colleagues used x-ray crystallography to describe the 3-D structure of the hypoxanthine phosphoribosyltransferase 1 protein and reported the effects of single amino acid substitutions on the stability and activity of hypoxanthine phosphoribosyltransferase 1 (33). Xu and colleagues described kinetic mechanisms of HPRT1 function (160). Jiralerspong and Patel provided a comprehensive review of regulation of the HPRT1 gene that includes both in vivo and in vitro approaches (80). Lowenstein provided a review of the prospects for gene therapy (93), and Young and Palmour discussed promises and limitations of gene research for HPRT1 deficiency (163). Gene Reviews provides a comprehensive review of HPRT1 deficiency, including metabolic aspects (106). Fu and colleagues examined genotype-phenotype correlations in Lesch-Nyhan disease (44). They summarized 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. Overall, the disease depends on how mutations influence enzyme activity. However, there are exceptions involving additional genetic and nongenetic factors that influence genotype-phenotype correlations (15).

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