Genetic defects of folate and cobalamin metabolism

Eur J Pediatr. 1998 Apr:157 Suppl 2:S60-6. doi: 10.1007/pl00014306.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Absorption
  • Amino Acid Metabolism, Inborn Errors / genetics
  • Amino Acid Metabolism, Inborn Errors / metabolism*
  • Animals
  • Coenzymes / metabolism
  • Fibroblasts / enzymology
  • Folic Acid / metabolism*
  • Homocysteine / metabolism*
  • Humans
  • Lysosomes / metabolism
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Oxidoreductases Acting on CH-NH Group Donors / deficiency
  • Tetrahydrofolates / metabolism
  • Transcobalamins / metabolism
  • Vitamin B 12 / metabolism*


  • Coenzymes
  • Tetrahydrofolates
  • Transcobalamins
  • Homocysteine
  • 5,6,7,8-tetrahydrofolic acid
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Vitamin B 12