GENETIC-DEFECTS OF FOLATE AND COBALAMIN METABOLISM

Deficient activity of all enzyme fan result from a defect in the conve rsion of the vitamin to a co-enzyme as well from an abnormal ape-enzym e or disturbed binding of co-enzyme to enzyme. Conversion of dietary v itamin to intracellular active co-enzyme can be complex and require ma ny physiological and biochemical processes including stomach release o f bound vitamin. intestinal uptake, carriers/transport blood transport , cellular uptake, intracellular release and intracellular compartment alisation. Disorders of malabsorption (food cobalamin malabsorption, i ntrinsic factor deficiency and abnormal enterocyte cobalamin processin g) and transport proteins (transcobalamin II deficiency. R-binder defi ciency) mostly lead to disturbed function of the two cobalamin requiri ng enzymes, methylmalonyl CoA mutase and methionine synthase. Defects of early steps of intracellular cobalamin (cblF cbl C/D) result in mar ked deficiencies of both cobalamin co-enzymes and homocystinuria combi ned with methylmalonic aciduria, Defective synthesis of adenosyl cobal amin in the cbl A/B defects leads to methylmalonyl CoA mutase. Isolate d methionine synthase deficiency is also classified as a cobalamin dis order due to its associated deficient formation of methylcobalamin. Fo late disorders include methylene-tetrahydrofolate reductase deficiency and glutamate formimino-transferase deficiency. In addition a heredit ary disorder of intestinal folate transport has been described. Less w ell established are disorders of dihydrofolate reductase. methenyl-tet rahydrofolate cyclohydrolase, and defects of cellular folate uptake.