VitaminB₁₂: Disorders of Absorption and Metabolism

Abstract

Derivatives of vitamin B 12 (cobalamin) are required for activity of two enzymes: methylmalonyl‐CoA mutase, which catalyses conversion of methylmalonyl‐CoA to succinyl‐CoA, and methionine synthase, which converts homocysteine to methionine. Cobalamin deficiency results in the accumulation of methylmalonic acid and homocysteine in blood and urine. Clinically, deficiency results in megaloblastic anaemia and subacute combined degeneration of the spinal cord, loss of sensation, ataxia, dementia and psychosis. Dietary cobalamin deficiency is rare in developed countries, except for individuals consuming a vegan diet. A more common cause of cobalamin deficiency is pernicious anaemia, an autoimmune disease that results in inability to absorb cobalamin from the intestine. A number of rare genetic disorders have been identified that result in either failure to absorb dietary cobalamin, to transport cobalamin from the intestine to cells that require it for metabolism or to convert intracellular cobalamin to one or both of its coenzyme derivatives, adenosylcobalamin and methylcobalamin. Key Concepts Cobalamin (vitamin B 12 ) is required for activity of two enzymes, methylmalonyl‐CoA mutase and methionine synthase, in mammalian cells. Cobalamin deficiency results in accumulation of methylmalonic acid and homocysteine in blood and urine. Clinically, deficiency is characterised by megaloblastic anaemia and/or neurological problems. Uptake of dietary cobalamin requires the binding protein intrinsic factor, secreted by parietal cells of the stomach, and the intestinal receptor cubam. Autoimmune destruction of parietal cells results in pernicious anaemia. Mutations in the genes encoding intrinsic factor or the components of cubam (cubilin and amnionless) result in heritable cobalamin malabsorption and signs of cobalamin deficiency. Peripheral cells take up cobalamin bound to the transport protein transcobalamin by carrier‐mediated endocytosis. Cells convert cobalamin to adenosylcobalamin, required by methylmalonyl‐CoA mutase, and methylcobalamin, required by methionine synthase. Rare mutations affecting genes involved in cobalamin metabolism result in decreased synthesis of either or both cobalamin derivatives. Mutations in certain transcription regulators can affect expression of genes encoding cobalamin metabolising enzymes, resulting in altered cobalamin coenzyme synthesis.