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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD004608-17
Application #
3310315
Study Section
Biochemistry Study Section (BIO)
Project Start
1975-06-01
Project End
1990-08-31
Budget Start
1985-09-30
Budget End
1986-08-31
Support Year
17
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Crutchfield, Susan R; Haas, Richard H; Nyhan, William L et al. (2008) 'Succinic semialdehyde dehydrogenase deficiency: phenotype evolution in an adolescent patient at 20-year follow-up'. Dev Med Child Neurol 50:880-1
Ko, F J; Nyhan, W L; Wolff, J et al. (1991) 3-Hydroxyisobutyric aciduria: an inborn error of valine metabolism. Pediatr Res 30:322-6
Hoffmann, G F; Sweetman, L (1991) O-(2,3,4,5,6-pentafluorobenzyl)oxime-trimethylsilyl ester derivatives for sensitive identification and quantitation of aldehydes, ketones, and oxoacids in biological fluids. Clin Chim Acta 199:237-42
Aramaki, S; Lehotay, D; Sweetman, L et al. (1991) Urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate and tiglylglycine after isoleucine loading in the diagnosis of 2-methylacetoacetyl-CoA thiolase deficiency. J Inherit Metab Dis 14:63-74
Hoffmann, G F; Sweetman, L; Bremer, H J et al. (1991) Facts and artefacts in mevalonic aciduria: development of a stable isotope dilution GCMS assay for mevalonic acid and its application to physiological fluids, tissue samples, prenatal diagnosis and carrier detection. Clin Chim Acta 198:209-27
Cochran, F B; Sweetman, L; Schmidt, K et al. (1990) Pyridoxine-unresponsive homocystinuria with an unusual clinical course. Am J Med Genet 35:519-22
Iden, P; Middleton, B; Robinson, B H et al. (1990) 3-Oxothiolase activities and [14C]-2-methylbutanoic acid incorporation in cultured fibroblasts from 13 cases of suspected 3-oxothiolase deficiency. Pediatr Res 28:518-22
Barshop, B A; Wolff, J; Nyhan, W L et al. (1990) Transcobalamin II deficiency presenting with methylmalonic aciduria and homocystinuria and abnormal absorption of cobalamin. Am J Med Genet 35:222-8
Gibson, K M; Aramaki, S; Sweetman, L et al. (1990) Stable isotope dilution analysis of 4-hydroxybutyric acid: an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria. Biomed Environ Mass Spectrom 19:89-93
Yoshida, I; Sweetman, L; Kulovich, S et al. (1990) Effect of lipoic acid in a patient with defective activity of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and branched-chain keto acid dehydrogenase. Pediatr Res 27:75-9

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