Introduction

Lesch–Nyhan disease, the most common and most thoroughly studied of the disorders of purine metabolism, was first described as a syndrome in 1964 (Lesch & Nyhan, 1964). The initial two patients were brothers, an early indication of the X-linked recessive nature of the disease, which shortly became evident with the study of the pedigrees of families with numbers of affected males (Nyhan et al., 1967). The older brother of the proband was in an institution with a diagnosis of mental retardation and cerebral palsy, when the younger brother was admitted with hematuria and found to have hyperuricemia and uricosuria and had bizarre and compulsive, self-mutilative biting. Both brothers exhibited involuntary choreoathetoid movements. A hallmark feature of the disease has continued to be loss of tissue resulting from biting or some other form of self-injurious behavior. Biochemical studies identified that the uric acid pool was enlarged and its turnover was abnormally rapid. The overproduction of purine from an intravenous glycine precursor was 20 times the normal value (Nyhan, 1968), whereas in adults with gouty arthritis the greatest rates of de novo synthesis of purines observed were twice the normal value.

The molecular defect is the virtually complete absence of activity of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT) (Fig. 24.1) (Seegmiller et al., 1967). HPRT catalyzes the reaction in which the purine bases, hypoxanthine and guanine, are converted in what has been referred to as a salvage or reutilization pathway to their respective nucleotides, inosinic acid (IMP) and guanylic acid (GMP).