This project integrates basic and clinical research in a "bench to bedside" approach to the challenges of human disease. Most disorders affecting the nervous system are characterized by a wide range of patient presentations, yet the factors contributing to this heterogeneity are often elusive. Gaucher disease, the most common of the sphingolipidoses, is studied as a prototype for many disorders affecting the nervous system because there is a broad spectrum of clinical diversity resulting from this recessively inherited enzyme deficiency. Gaucher disease affects approximately 10,000 to 20,000 Americans and is more common among Ashkenazi Jews. Clinical, molecular, and biochemical studies in humans and animals are used to enhance our understanding of heterogeneity in Gaucher disease and our ability to develop rational therapy for patients. The techniques, insights, and experience gained are then applied to other less characterized disorders and ultimately to the challenges of complex psychiatric illnesses. Our clinical and molecular studies have shown that there is significant genotypic heterogeneity among clinically similar patients, and that the vastly different phenotypes encountered among patients with Gaucher disease, as well as with many other disorders, are not adequately predicted by genotype. Thus we are exploring other genetic or environmental factors contributing to the phenotypes seen. Recombination events within and around the glucocerebrosidase locus, and newly discovered contiguous genes, may potentially have a critical role. Transgenic and knock-out mice are used to facilitate our understanding of the pathogenesis and treatment of lysosomal storage disorders and the phenotypic consequences of specific genotypes. Murine models led to the recognition of a new lethal human Gaucher phenotype, the involvement of the substrate glycosylsphingosine, the role of glucocerebrosidase in skin morphology and function, and the identification of a novel contiguous gene, metaxin. We are also focusing on patients with Gaucher disease and atypical manifestations including parkinsonism, myoclonic epilepsy, cardiac involvement and collodion skin. Understanding the mechanisms leading to these diverse phenotypes will provide insights relevant to other disorders.