Excerpt from Lesch-Nyhan Syndrome

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Background

Michael Lesch and William Nyhan provided the first detailed clinical description of Lesch-Nyhan syndrome in 1964. The enzymatic defect associated with Lesch-Nyhan syndrome, deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), was discovered by Seegmiller and colleagues in 1967. The gene encoding the enzyme was cloned and sequenced by Friedmann and colleagues in 1985.

Lesch-Nyhan syndrome is a genetic disorder associated with 3 major clinical elements. These elements include overproduction of uric acid, neurological disability, and behavioral problems. The overproduction of uric acid is associated with hyperuricemia. If left untreated, it can produce nephrolithiasis with renal failure, gouty arthritis, and solid subcutaneous deposits known as tophi. The neurological disability encompasses a spectrum of extrapyramidal signs, including dystonia, choreoathetosis, and occasionally ballismus. Some patients also develop pyramidal signs, such as spasticity and hyperreflexia. The behavioral problems include cognitive dysfunction and aggressive and impulsive behaviors. Nearly all patients also develop persistent and severe self-injurious behavior.

Treatment of the condition is limited. Allopurinol is useful to control the overproduction of uric acid and reduces the risk of nephrolithiasis and gouty arthritis. Few treatments have proved consistently helpful for the neurological or behavioral difficulties. Spasticity is managed with a combination of baclofen and benzodiazepines, while the behavioral abnormalities are best managed by a combination of behavioral modification techniques and medications.

Pathophysiology

The metabolic basis for the overproduction of uric acid has been studied extensively. HPRT normally plays a key role in the recycling of the purine bases, hypoxanthine and guanine, into the purine nucleotide pools (see Image 1). In the absence of HPRT, these purine bases cannot be salvaged, and instead are degraded and excreted ultimately as uric acid. In addition to the failure of purine recycling, the synthetic rate for purines is accelerated markedly, presumably to compensate for purines lost by the failure of the salvage process. The failure of recycling together with the increased synthesis of purines result in a dramatic overproduction of uric acid.

The increased production of uric acid leads to hyperuricemia. Since uric acid is normally near its physiological limit of solubility in the body, the persistent hyperuricemia increases the risk of uric acid crystal precipitation in the tissues to form tophi. Uric acid crystal deposition in the joints produces a marked inflammatory reaction and gouty arthritis. The kidneys respond to the hyperuricemia by increasing its excretion into the urogenital system. The increased excretion of uric acid increases the risk of forming urate stones in the urinary collecting system. These stones may be passed as a sandy sludge or as larger particles that may obstruct urine flow and increase the risk for hematuria and urinary tract infections.

The pathogenesis of the neurological and behavioral features is incompletely understood. Neurochemical and neuroimaging studies have demonstrated significant abnormalities of dopamine neuron function in the basal ganglia that might account for the abnormal extrapyramidal neurological signs and many of the behavioral anomalies. However, the mechanism by which HPRT deficiency influences the basal ganglia, and particularly the dopamine systems, remains unknown.

Frequency

International

The reported worldwide prevalence is 1 case per 380,000 population.

Mortality/Morbidity

Few patients live beyond 40 years. Despite the use of allopurinol to control hyperuricemia, some patients still succumb to the consequences of persistent nephrolithiasis, such as renal failure or urosepsis. Other patients experience progressive dysphagia and die after aspiration and pneumonia. Sudden unexpected death is common, even on a background of an apparently stable medical condition. The reasons for sudden death remain unknown, though respiratory failure from cervical pathology or laryngospasm are considered leading possibilities.

Race

The disease has been reported for most races, with approximately equal rates for most ethnic groups.

Sex

This is an X-linked recessive disorder; therefore, nearly all cases are in males. Only rarely has it been reported in females.

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