Introduction
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, neurologic 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 neurologic disability is dominated by dystonia but may include choreoathetosis, ballismus, or pyramidal signs, such as spasticity and hyperreflexia. The behavioral problems include cognitive dysfunction and aggressive and impulsive behaviors. Patients with the classic syndrome also develop persistent and severe self-injurious behavior.
In addition to the classic clinical syndrome, patients with less severe disease and partial syndromes are increasingly recognized. In these milder variants, self-injury may not occur, cognition may be normal, or dystonia may be mild or even absent. These patients are identified by the overproduction of uric acid due to HPRT deficiency.
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 proven consistently helpful for the neurologic 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
HPRT normally plays a key role in the recycling of the purine bases, hypoxanthine and guanine, into the purine nucleotide pools (see Media file 1). In the absence of HPRT, these purine bases cannot be salvaged, and instead are degraded and excreted as uric acid. In addition to the failure of purine recycling, the synthetic rate for purines is accelerated, presumably to compensate for purines lost by the failure of the salvage process. The failure of recycling together with the increased synthesis of purines is the basis for the overproduction of uric acid.
The increased production of uric acid leads to hyperuricemia. Since uric acid is 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 an inflammatory reaction and gouty arthritis. The kidneys respond to the hyperuricemia by increasing its excretion into the urogenital system, increasing 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.
Clinical
History
- Most patients present at age 3-12 months with delayed motor development, most commonly hypotonia or failure to reach normal motor milestones. Between ages 6 and 18 months, abnormal involuntary movements indicative of extrapyramidal dysfunction become more prominent; some patients also develop corticospinal signs. Patients may often receive a diagnosis of cerebral palsy. After an initial period of progression that may last until 3-6 years of age, motor disability does not continue to progress.
- A smaller number of patients presents with complications related to the overproduction of uric acid. Sometimes there is a history of "orange sand" in the diapers, which is caused by uric acid crystalluria and microhematuria. Other patients may present with renal failure or frank hematuria, resulting from nephrolithiasis.
- Though self-injurious behavior is rarely the presenting feature of the illness, it eventually develops in nearly all cases. The emergence of the behavior often provides the essential clue to the diagnosis in a case with known developmental delay or hyperuricemia.
Physical
- The most salient feature of the general physical examination is growth retardation. Somatic growth is affected more than head circumference; bone age is affected only slightly. Testicular atrophy is common. Puberty is often delayed or absent.
- Neurologically, cognitive function is impaired, with average intelligence quotient (IQ) values of approximately 60. Basic sensory functions appear largely intact, though motor function is compromised severely. All patients exhibit severe generalized dystonia. Some also exhibit other extrapyramidal features, including choreoathetosis, opisthotonic spasms, and ballismus. Approximately one quarter also display pyramidal features, including hyperreflexia and ankle clonus. The severity of the neurologic dysfunction precludes normal ambulation, and all patients are wheelchair bound.
- Behavioral problems are also prominent. Frequent attempts toward self-injury may be evident. Partial amputations of the fingers, lips, tongue, or oral mucosa, resulting from self-biting, are common (see Media files 2-3). Serious injuries or scarring from repetitive self-abrasion or hitting also may result. In addition to self-injurious behavior, many patients display compulsive behaviors that often are interpreted as signs of aggression. These include hitting, spitting, coprolalia, copropraxia, and manipulative behavior.
Causes
- This is a genetic disorder caused by mutations in the HPRT gene on the X chromosome.
- The mutations are heterogenous, including single base substitutions, deletions, insertion, or substitutions (see Media file 4).
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References
Alford RL, Redman JB, O'Brien WE, et al. Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenat Diagn. Apr 1995;15(4):329-38. [Medline].
Jinnah HA, Friedmann T. Lesch-Nyhan disease and its variants. In: Scriver CR, Sly WS, Childs B, Beaudet AL, et al, eds. The Molecular and Metabolic Bases of Inherited Disease. 6th ed. New York, NY: McGraw-Hill; 2000:Chapter 107.
Jinnah HA, De Gregorio L, Harris JC, et al. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res. Oct 2000;463(3):309-26. [Medline].
Jinnah HA, Visser JE, Harris JC, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. May 2006;129(Pt 5):1201-17. [Medline].
Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med. Apr 1964;36:561-70. [Medline].
Nyhan WL, Vuong LU, Broock R. Prenatal diagnosis of Lesch-Nyhan disease. Prenat Diagn. Oct 2003;23(10):807-9. [Medline].
Visser JE, Bar PR, Jinnah HA. Lesch-Nyhan disease and the basal ganglia. Brain Res Brain Res Rev. Apr 2000;32(2-3):449-75. [Medline].
Further Reading
Keywords
HPRT deficiency, hypoxanthine-guanine phosphoribosyl transferase, Kelley-Seegmiller syndrome, Lesch-Nyhan disease, overproduction of uric acid, neurologic disability, behavioral problems, hyperuricemia, nephrolithiasis with renal failure, gouty arthritis, tophi, dystonia, choreoathetosis, ballismus, spasticity, hyperreflexia, cognitive dysfunction, aggressive behaviors, impulsive behaviors, self-injurious behavior
