Essential tremor (ET) is one of the most prevalent adult neurological disorders. Despite this, several fundamental clinical and genetic issues remain unknown: (1) The extent of familial aggregation is not known. (2) There are few quantitative data on the natural progression of disease, and the associations between disease progression, tremor distribution and tremor severity are not known. (3) There are few data on whether the degree of familial aggregation of ET is greater for certain subtypes of ET than for others (genetic heterogeneity). (4) Data on the mode of inheritance are almost exclusively derived from service or clinic-based studies, which may be biased towards an apparent autosomal dominant mode of inheritance. Additionally, all studies of this question have examined ethnically-homogeneous populations. The study proposal is the first with a case-control community-based shielded (blinded) design, and has the following aims: (1) to determine the extent of familial aggregation of ET, (2) to analyze the natural history of ET, and associations between different clinically-defined subtypes of ET (subtypes will be based on clinical features such as tremor distribution, severity, and age of onset), (3) to compare different clinically-defined subtypes of ET in terms of the extent of increased risk of ET within families, and (4) to test genetic and nongenetic models that could explain the familial distribution of ET. In families with three or more affected cases, blood specimens will be drawn from study subjects for future linkage analysis. Subjects will be selected from a community-based study of neurological disease in a multiethnic community in Washington Heights-Inwood, northern Manhattan, New York (NIH Grant # PO-1-AG07232-06, R. Mayeux, P.I.). Thirty-seven cases with ET, 37 matched controls, and 666 relatives of these cases and controls will be interviewed, examined, and videotaped using a standardized protocol. Data on disease characteristics and progression will be collected. Diagnoses will be assigned by two neurologists using a diagnostic protocol utilized in our previous study. Electrophysiological studies (tremor analysis) will be used to validate a proportion of all diagnoses. This applicant is trained as an academic clinical neurologist with specialization in clinical movement disorders and neuroepidemiology. This grant will enable him to develop an academic career in neurology and genetic epidemiology by allowing him (1) to collaborate with neurologists and genetic epidemiologists in the Sergievsky Center, (2) to learn methods of genetic epidemiology. including segregation analysis and eventually. linkage analysis, (3) to continue courses in the Columbia University School of Public Health. Drs. W. Allen Hauser, Ruth Ottman, Richard Mayeux and Stanley Fahn, all internationally recognized either within the areas of Neuroepidemiology or Movement Disorders, will provide invaluable guidance in these studies.
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