Inherited errors of cobalamin metabolism and their management.

Cobalamins are essential biological compounds structurally related to haemoglobin and the cytochromes. Although the basic cobalamin molecule is only synthesized by micro-organisms, all mammalian cells can convert this into the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). AdoCbl is the major form in cellular tissues, where it is retained in the mitochondria. MeCbl predominates in blood plasma and certain other body fluids such as breast milk; in cells MeCbl is found in the cytosol. Inherited disorders of cobalamin metabolism are single gene defects, transmitted as recessive traits. They affect absorption, transport or intracellular metabolism of cobalamin. At least 12 different mutations are known, including defects or deficiencies of IF, IF-receptor and TCII, MM-CoA mutase and of the various reductases and synthases required for synthesis of AdoCbl and MeCbl. These have been designated cblA to cblG. Abnormalities are detectable by urine and plasma assays of methylmalonic acid and homocysteine, and plasma and erythrocyte analysis of cobalamin coenzymes, which can reveal deficiencies of MeCbl or AdoCbl. Fibroblast studies discriminate between closely similar defects. In man, AdoCbl is required in only two reactions: the catabolic isomerization of MM-CoA to succinyl-CoA and interconversion of alpha- and beta-leucine. MeCbl is required in the anabolic transmethylation of homocysteine to methionine. Intestinal absorption of cobalamin requires the glycoproteins TCI and IF from the stomach and IF-cobalamin receptors in the ileum. Cobalamin is transported to cells bound to a polypeptide, TCII, is captured by surface receptors and absorbed by endocytosis. The complex is then split in the lysosomes, cobalamin is released and the coenzymes are synthesized. In plasma, 80-90% of the cobalamin is bound to TCI, whose function is uncertain. Megaloblastic anaemia at birth or in the first few weeks of life is a rare but serious event. Myelopathy and developmental delay, with or without seizures may also occur without anaemia. If urine and light-protected blood samples are collected and sent to an appropriate metabolic unit, an inborn error of cobalamin metabolism, including TCII deficiency in which the serum B12 may be normal, can quickly be diagnosed. IF deficiency or Imerslund-Gräsbeck disease usually presents with signs of cobalamin deficiency within the first year of life and can be diagnosed by absorption studies. Current treatment involves dietary protein restriction and/or parenteral OHCbl and the prognosis is very variable. Since lack of MeCbl leads to depressed DNA synthesis affecting rapidly dividing cells in the brain and elsewhere, treatment with this coenzyme should be considered at the earliest stage in appropriate cases.(ABSTRACT TRUNCATED AT 400 WORDS)