Lesch-Nyhan syndrome is an X-linked recessive inborn error of purine metabolism caused by absence of, or deficiency in, hypoxanthine-guanine phosphoribosyl transferase (HPRT). HPRT metabolizes hypoxanthine and guanine to uric acid. First described in two brothers by Lesch and Nyhan in 1964, the disorder is fortunately rare, occurring in less than 1 in 200,000 births. It affects almost only males and is apparently equally distributed geographically and among ethnic groups. The disease is either inherited or arises through genetic mutation. The expression of the gene is fully recessive, making the disorder virtually exclusive to males by transmission from their mothers. Females can be carriers, but rarely exhibit the disease. A few reported cases in females are believed to have occurred through genetic mutation.
Owing to its similarities to other brain disorders such as cerebral palsy, Lesch-Nyhan should be diagnosed through appropriate laboratory tests. These include HPRT-activity testing in tissue samples, prenatal enzyme assay, and DNA analysis through amniocentesis or chorionic villus sampling.
The disorder is characterized by numerous neurological-behavioral motor abnormalities, the most horrific being severe and chronic self-injurious and aggressive behaviors. Self-injurious behaviors (SIBs) are so persistent and potentially damaging that physical restraint is generally required. The most frequent SIBs are hand biting and lip chewing, which often lead to considerable tissue loss. Because pain perception is normal, affected children may scream while emitting SIBs and beg to be physically restrained. Lip chewing can be so self-mutilating that teeth extraction is necessary, even in infancy. Other motor dysfunctions include choreoathetosis (slow, wormlike large muscle movements), spasticity, hypertonicity, and articulation and chewing-swallowing problems. Although mental retardation has been seen as a regular feature of LeschNyhan syndrome, the motoric dysfunctions make interpretation of standard intelligence test scores difficult. Some affected boys have shown normal memory skills, range of emotions, concentration abilities, self-awareness, and social skills, suggesting that the degree of general cognitive deficiency may often be overestimated. Sensory functioning appears to be normal. Morales presents a detailed description of characteristics of Lesch-Nyhan individuals.
The extreme overproduction of uric acid results in gout, hyperuricemia, and other manifestations of renal dysfunction.
Lesch-Nyhan individuals appear normal at birth. The earliest sign of the disorder occurs at about 10 to 30 days of age when high levels of uric acid, indicative of renal dysfunction, lead to orange crystalline deposits in diapers. Affected infants show normal motor development usually until 3 to 6 months of age, when they begin to show marked hypotonicity, delays in motor development, and loss of previously acquired motor skills. At about 6 to 12 months of age, hypotonicity is replaced by hypertonicity: arching of the back, poor head control, choreoathetosis, spasticity, and other involuntary motor movements. Affected individuals are generally unable to sit or stand without assistance. Speech is greatly delayed and limited.
Self-mutilation begins at about 2 years of age and may lead to differential diagnosis from cerebral palsy. Self-injurious and aggressive behaviors become more severe and destructive with age. The earlier the onset of SIBs, the worse they become over time. Motor dysfunction is also progressive, with greatest deterioration occurring in later childhood; hip dislocation and leg scissoring may result in serious injury unless the individual is closely monitored.
Allopurinol effectively reduces HPRT-based hyperuricemia and its various renal effects, including gout, but does not reduce neurologic abnormalities. Serotonin reuptake inhibitors, used to correct dopamine and serotonin levels, have shown short-term improvements, but over time, effectiveness significantly diminishes. Benzodiazepines may be prescribed for behavior control, although they do not have long-term effects on self-injury.
Treatment of motor dysfunctions has limited effect. The best preventative strategy for self-injurious and aggressive behavior has been stress reduction and protective restraint. Behavior modification successfully reduces such behaviors in some cases, as described by Olson and Houlihan, but no commonly effective treatment is available. Differential reinforcement of other (DRO) behaviors and differential reinforcement of incompatible (DRI) behaviors are perhaps most effective and relatively unlikely to have iatrogenic effects. Extinction, although sometimes effective, is both slow and risks danger of bursts of SIBs owing to frustration. Punishment with electric shock actually increased SIBs in one case, whereas punishment with spraying vinegar solutions in combination with reinforcement for other behaviors reduced SIBs in another. Particularly with explicit programming, generalization across settings and long-term effects may occur.
Research suggests that self-mutilation is based on reduced dopamine-neuron function and norepinephrine turnover. Recent development of HPRT-deficient animal models, as well as research with affected humans, may lead to understanding of the biochemical basis of self-mutilation and more effective treatment.
- Luiselli, K., Matson, J. L., & Singh, N. N. (Eds.). (1992). Self-injurious behavior. New York: Springer-Verlag.
- Morales, P. (1999). Lesch-Nyhan syndrome. In S. Goldstein & C. R. Reynolds (Eds.), Handbook of neurodevelopmental and genetic disorders of children, pp. 478–498. New York: Guilford.
- Nyhan, W. (1973). The Lesch-Nyhan syndrome. Annual Review of Medicine, 24, 41–60.
- Olson, L., & Houlihan, D. (2000). A review of behavioral treatments used for Lesch-Nyhan syndrome. Behavior Modification, 24, 202–222.