Mouse and rat
Researchers have made a mouse that carries a genetic defect in the same gene that causes Lesch-Nyhan disease. They have some of the same biochemical defects seen in affected people. They can’t recycle hypoxanthine and guanine, and there is a marked increase in de novo purine synthesis. The mutant mice do not suffer from gout or kidney stones due to increased uric acid; they have an enzyme that humans do not. This enzyme is uricase, and it prevents uric acid from becoming a problem by degrading it into allantoin.
The mice also have some of the same changes in brain chemistry seen in affected people. There is a significant loss of dopamine in the basal ganglia, but other neurochemical messengers are normal. These mutant mice have therefore been very valuable for studying the relationship between HPRT deficiency and dysfunction of basal ganglia dopamine systems.
Despite the metabolic and neurochemical abnormalities, the mutant mice do not exhibit neuromotor or behavioral abnormalities similar to those seen in people with Lesch-Nyhan disease. The reason they are spared these aspects of the disease remain unclear. It is possible that they have other metabolic pathways that compensate for the loss of HPRT, or that their brains are less sensitive to the effect of HPRT deficiency. Further research to get answers to this question may provide clues to factors that may help protect people against the same problems.
Other researchers have reproduced some of the features of Lesch-Nyhan disease in rats. If the basal ganglia dopamine system of a rat is damaged at a very young age, the rat grows up almost normally. However, treatment of the rat with dopamine stimulants results in the emergence of self-injurious biting behavior. These rats have taught us that early injury to basal ganglia dopamine systems may be responsible for this problem in Lesch-Nyhan disease.
Lessons learned from these rats have suggested a novel form of treatment. If we can restore the lost dopamine, it may be possible to eliminate self-injury in Lesch-Nyhan disease. So far, attempts to do this have not been successful. One possibility is that restoration of dopamine after the problem has emerged will not work because it is too late. Another strategy is to prevent the loss of dopamine, or supply it at a very early age before self-injury begins.