This proposed research concerns the study of the genetic, biochemical, clinical and pathological aspects of human hereditary metabolic disorders of amino acids, organic acids and related compounds, particularly those causing mental retardation and other neurologic and metabolic complications. Specific projects include 1) delineation of genetic complementation groups in sulfite oxidate deficiencey and in its molybdenum cofactor deficiency, and further characterization of a soluble corrective factor which is produced by one mutant class and which is able to reconstitute sulfite oxidase activity in certain other mutant classes; 2) study of glutamate dehydrogenase deficiency in Joseph's disease; 3) investigation of homocitrulline metabolism and ornithine motochondrial transport in the syndrome of hyperornithinemia, hyperammonemia and homocitrullinuria; 4) immunoblot analysis of ornithine aminotransferase in one type of hyperornithinemia associated with liver disease; 5) investigation of amino acid metabolism in neuronal and glial cells, and development of a model for the study of brain metabolism in relation to hereditary metabolic diseases; 6) studies of myelination, neurotransmitter deficiency, and molecular defects in PKU; 7) determination of the frequency and natural history of ovarian failure in galactosemia and its variants, and determination of the status of galactose metabolism in ovarian tissue; and 8) correlation of enzymatic and biochemical findings with clinical outcome in argininosuccinic aciduria. For the majority of these studies cultured cells including fibroblasts, lymphoblasts, and established brain cell lines will be used for enzymatic and genetic analyses. In some projects, blood, spinal fluid and urine or liver and ovarian tissue will be utilized. Clinical studies will involve the noninvasive techniques of nuclear magnetic resonance (NMR) imaging and ultrasonography, in addition to psychometric testing and evaluation of the effects of dietary therapy. The proposed research is expected to yield important information regarding the genetic mechanisms and the pathogenesis of the neurologic and other abnormalities in the hereditary metabolic disorders studied. This information is essential in evaluating current therapeutic regimens and in designing improved treatment. Using cultured brain cells will open a new area for the study of amino acid metabolism in relation to neuronal functions in both normal and diseased states.
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