Lesch-Nyhan disease: from mechanism to model and back again

Abstract

Lesch-Nyhan disease (LND) is a rare inherited disorder caused by mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT). LND is characterized by overproduction of uric acid, leading to gouty arthritis and nephrolithiasis. Affected patients also have characteristic neurological and behavioral anomalies. Multiple cell models have been developed to study the molecular and metabolic aspects of LND, and several animal models have been developed to elucidate the basis for the neurobehavioral syndrome. The models have different strengths and weaknesses rendering them suitable for studying different aspects of the disease. The extensive modeling efforts in LND have questioned the concept that an 'ideal' disease model is one that replicates all of its features because the pathogenesis of different elements of the disease involves different mechanisms. Instead, the modeling efforts have suggested a more fruitful approach that involves developing specific models, each tailored for addressing specific experimental questions.

Fig. 1.

Validation of hypotheses versus validation of exploratory findings. (A) Experimental findings from human studies often generate hypotheses that cannot be tested in humans. Surrogate experimental models can be very useful to validate these hypotheses. For example, both animal and tissue culture models have been exploited to validate the hypothesis that dopamine loss in the LND brain results from degeneration of dopaminergic axonal projections in LND. (B) Surrogate experimental models can be used in exploratory studies to discover novel directions. Ideally, these findings should be validated by returning to human studies to ensure that they are relevant to the disease being studied. For example, recent findings from both animal and tissue culture models have suggested a defect in the developmental programming of the dopamine neuron neurochemical phenotype. These findings must now be validated by seeking similar defects in selected studies of the LND brain.

Fig. 2.

The roles of different surrogate experimental models in LND. The blue boxes depict the sequence of events that are thought currently to be involved in the pathogenesis of self-injurious behavior in LND. Tissue culture models have been particularly useful in elucidating proximal steps of the pathogenic pathway involving the effects of HPRT deficiency on purine metabolism. Further, some neuronal models have been useful in addressing the steps relating to dopamine neuron dysfunction, but no tissue culture model is suitable for addressing the more complex physiological interactions that occur among different neural elements of the basal ganglia, which potentially lead to the behavioral defects in the more distal steps of the pathway. Similarly, the HPRT-deficient mouse model has been useful for elucidating the more proximal steps in this pathway in an in vivo setting, but it has not been useful for understanding the behavioral abnormality. However, the neonatal dopamine lesion model has been more useful in distal steps of the pathway, beginning with dopamine lesions and ending with expression of the behavior. Each model has characteristics that might render it particularly well suited for studying specific steps in the pathway. There is no ‘ideal’ model that combines all of these strengths, but proper selection of the most appropriate model can address most experimental questions.