This project in human biochemical genetics is concerned with the study of biochemical manifestations of heritable disease. It is devoted to the detection and definition of new metabolic diseases and to the study of metabolic interrelations in these and other metabolic disorders. These interrelations of intermediary metabolism are related to the pathogenesis of the clinical manifestations of these diseases. They related particularly to the development of central nervous system function and to aberrations in this developmental process. It is through studies in this area that methods of treatment for some of these diseases may be developed. This laboratory has been involved in the definition of previously unrecognized inborn errors of metabolism, including the ketotic hyperglycinemia syndrome and hyperuricemia with hypoxanthine-guanine phosphoribosyl transferase deficiency, as well as more recently of transient hyperammonemia of the newborn and a new syndrome of methylmalonic acidemia and homocystinuria in the breast fed infant of the strictly vegan female. Studies in progress are focused on these disorders that present with overwhelming illness in the very young infant. They are particularly focused on the organic acidemias. Techniques of organic acid analysis include gas chromatography-mass spectrometry to define in detail the abnormal chemistry of body fluids in these patients. Techniques of enzyme analysis pursue the molecular defect in tissues and in fibroblasts in cell culture. Studies in animals are undertaken to pursue mechanisms of pathogenesis. A particular emphasis is proposed on the biotin-responsive deficiencies of multiple carboxylases. The search for other new metabolic diseases will also actively be pursued.
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