The clinical study of human genetic disorders that affect the nervous system provides foundation for the development of improved diagnostic techniques and strategies for therapy. This goal is greatly facilitated by having a comprehensive knowledge of the biochemistry and clinical heterogeneity of the disorder. Gaucher disease, the most common sphingolioidosis, has a high priority as a model for gaining insight into this group of neurogenetic disorders because of the occurrence of both neuronopathic and non- neuronopathic phenotypes as well as the broad spectrum of clinical diversity within the major types of the disorder. Once the pathophysiologic mechanisms of systemic involvement are understood, the therapy of nervous system dysfunction may be more rationally approached. Basic research on glucocerebrosidase, the enzyme deficient in Gaucher disease, has generated a more detailed understanding of the structure, biosynthesis, intracellular routing, and turnover of the enzyme. These studies will complement other studies within our branch focusing on the investigation of the potential and efficacy of gene transfer as a therapeutic approach. The use of recombinant DNA technologies to develop an appropriate animal model and to produce large amounts of both normal and mutant human proteins is being pursued.
