title: Genetic defects of folate and cobalamin metabolism.
abstract: Deficient activity of an enzyme can result from a defect in the conversion of the vitamin to a co-enzyme as well from an abnormal apo-enzyme or disturbed binding of coenzyme to enzyme. Conversion of dietary vitamin to intracellular active co-enzyme can be complex and require many physiological and biochemical processes including stomach release of bound vitamin, intestinal uptake, carriers/transport, blood transport, cellular uptake, intracellular release and intracellular compartmentalisation. Disorders of malabsorption (food cobalamin malabsorption, intrinsic factor deficiency and abnormal enterocyte cobalamin processing) and transport proteins (transcobalamin II deficiency, R-binder deficiency) mostly lead to disturbed function of the two cobalamin requiring enzymes, methylmalonyl CoA mutase and methionine synthase. Defects of early steps of intracellular cobalamin (cblF, cbl C/D) result in marked deficiencies of both cobalamin co-enzymes and homocystinuria combined with methylmalonic aciduria. Defective synthesis of adenosyl cobalamin in the cbl A/B defects leads to methylmalonyl CoA mutase. Isolated methionine synthase deficiency is also classified as a cobalamin disorder due to its associated deficient formation of methylcobalamin. Folate disorders include methylene-tetrahydrofolate reductase deficiency and glutamate formimino-transferase deficiency. In addition a hereditary disorder of intestinal folate transport has been described. Less well established are disorders of dihydrofolate reductase, methenyl-tetrahydrofolate cyclohydrolase, and defects of cellular folate uptake.
authors.affiliation: University Children's Hospital, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Fowler
mesh_terms: D000042:Absorption; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003067:Coenzymes / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D005492:Folic Acid / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000172:deficiency; D013763:Tetrahydrofolates / Q000378:metabolism; D014155:Transcobalamins / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism*
chemical_list: D003067:Coenzymes; D013763:Tetrahydrofolates; D014155:Transcobalamins; D006710:Homocysteine; C030371:5,6,7,8-tetrahydrofolic acid; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12