There are a number of neurological diseases whose etiology is unknown, but whose biochemical characteristics imply mitochondrial involvement. For diseases which are heritable, a primary mitochondrial defect suggests the possibility that the genetic factor may be cytoplasmic rather than nuclear. I propose that such a possibility can be assessed by screening patients for a defect in mitochondrial protein synthesis as follows: 1. A limited number of patients with diseases which are most likely to involve a primary mitochondrial defect will be selected. These inlcude the heritable diseases of lactate and pyruvate dysfunction, e.g., Leigh's disease, congenital lactic acidosis, and cerebellar ataxia; and cerebro-hepato-renal syndrome. Primary screening for defects of mitochondrial protein synthesis will be carried out on cultured skin fibroblasts from the patients. Secondarily, tissue biopsies obtained for other diagnostic purposes will be used as available. 2. Mitochondrial protein synthesis will be assayed and products of mitochondrial translation will be analyzed. Mitochondrially-synthesized proteins will be labeled with 35S-methionine and analyzed by SDS-polyacrylamide slab gel electrophoresis and autoradiography. This study will provide information for the first time on the role of mitochondrial protein synthesis in heritable disorders of mitochondrial dysfunction. The labeling and analysis of mitochondrially-synthesized proteins have been well worked out, and make feasible a rapid initial assessment of the importance of mitochondrial genetics in neurological disease.