A bench to bedside approach is used in our studies of human genetic disorders, integrating both basic and clinical research. Most inherited diseases 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 because of the 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. Natural history studies as well as molecular and biochemical evaluations 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 can then be applied to other Mendelian disorders and ultimately to the challenges of complex illnesses[unreadable] [unreadable] 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 and are studying factors involved in the regulation of glucocerebrosidase. 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. Comparative genomics and protein modeling studies utilizing the three dimensional structure of the enzyme may also lead to a better understanding of the mutant protein. We also focus on patients with Gaucher disease and atypical manifestations including parkinsonism, myoclonic epilepsy, cardiac and renal involvement and collodion skin. Understanding the mechanisms leading to these diverse phenotypes may help in the identification of modifier genes and will provide insights relevant to other disorders.[unreadable] [unreadable] A major direction in our research relates to growing evidence implicating an association between Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, and parkinsonism. This includes clinical studies of Gaucher probands, neuropathologic evaluations, family studies and screening of tissues and DNA samples from subjects with Parkinson disease. Rare patients with Gaucher disease and parkinsonism have been identified, and studies of such patients demonstrates many shared clinical features, yet many different genotypes. Currently, prospective studies of these subjects as well as affected or at-risk relatives are underway, and include Positron Emission Tomography studies of the brain to determine whether there are specific characteristic changes. Neuropathology from several of these cases demonstrated large, immunoreactive Lewy bodies in the substantia nigra and changes in brain hippocampal layers CA2-CA4, a region of vulnerability also in diffuse Lewy body disease. Although parkinsonism is relatively common, deriving from multiple different causes, the shared clinical and neuropathologic findings in this subgroup suggested a related etiology. Furthermore, family histories of families of patients with Gaucher disease identified several carrier relatives who developed parkinsonism. This prompted an examination of the glucocerebrosidase gene in probands with Parkinson disease. Complete gene sequencing of GBA was initially performed in brain samples from individuals who died carrying the clinical and/or pathologic diagnosis of Parkinson disease and demonstrated that a significant number had mutations in GBA. Glucocerebrosidase mutations were also identified in samples from patients with the diagnosis diffuse Lewy Body dementia. Our studies indicate that an alteration in glucocerebrosidase, even in heterozygotes, may contribute to a vulnerability to synecleinopathies. This finding has been replicated in other large Parkinson cohorts, suggesting that mutations in glucocerebrosidase could be a frequent inherited risk factor associated with parkinsonism. A multi-center meta-analysis of these different studies is in progress. This project demonstrates how studies of a rare metabolic disorder, Gaucher disease, may provide a window into both the genetics and pathogenesis of a common complex disorder, Parkinson disease.[unreadable] [unreadable] Another important goal is to develop new treatment strategies for patients. Enzyme replacement therapy for Gaucher disease with imiglucerase has been shown to be clinically effective, but its extremely high cost is of considerable concern both to the public and to health care providers. A potential alternative therapy is the use of small molecules that may function as chemical chaperones that can stabilize and enhance the patient s mutant enzyme. This approach is being explored by studies of the trafficking of glucocerebrosidase and investigations of whether small molecules may enhance the delivery of mutant glucocerebrosidase to the lysosome. In collaboration with Dr. Chris Austin (NHGRI), we have screened large libraries of compounds and have identified several three different structural classes of chemical chaperones that may serve as the basis for new therapies.
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