Summary
Vitamin B12 (Cbl) is needed for just two metabolic reactions in man, the methylation of homocysteine to methionine (cofactor methyl-Cbl) and the conversion of methylmalonyl-CoA to succinyl-CoA (cofactor adenosyl-Cbl). A complex sequence of processes is required to convert dietary Cbl to its cofactors and to correctly deliver them to the target enzymes. A wide range of acquired or hereditary disorders of absorption, transport and intracellular processing of Cbl are known, resulting in combined methylmalonic aciduria and homocystinuria or each in isolation. Seventeen distinct genetic disorders have been identified involving transcription factors, carrier proteins, receptors, membrane proteins, molecular chaperones and enzymes, and the genes have been characterised for each of these, although the exact function of some of the proteins remains to be elucidated. Main clinical hallmarks of these disorders are haematological and neurological disease of varying severity. Diagnosis centres on measurement of the two precursors of the Cbl enzymes, methylmalonic acid and homocysteine, together with measurements of other parameters such as total vitamin B12, holotranscobalamin, 3-hydroxypropionic acid and methylcitric acid, C3-acylcarnitine and methionine. Absorption and transport defects respond well to treatment with Cbl. Intracellular processing defects also respond to Cbl, but biochemical and clinical abnormalities may not fully resolve, and long-term outcome can be poor. Prenatal diagnosis can be reliably performed in those disorders where this is indicated.
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Baumgartner, M.R., Froese, D.S. (2022). Disorders of Cobalamin Metabolism. In: Blau, N., Dionisi Vici, C., Ferreira, C.R., Vianey-Saban, C., van Karnebeek, C.D.M. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-67727-5_28
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