Cobalamin (vitamin B12) is an essential water-soluble cofactor required for two enzymatic reactions in human cells: the cytosolic remethylation of homocysteine to methionine by methionine synthase, and the mitochondrial isomerization of methylmalonyl-coenzyme A (CoA) to succinyl-CoA by methylmalonyl-CoA mutase. Inherited disorders affecting affecting intestinal absorption, plasma transport, cellular uptake, or intracellular processing produce a spectrum of multisystem diseases that present from the neonatal period through adulthood with hematologic, neurologic, psychiatric, ophthalmologic, renal, hepatic, thromboembolic, and cardiovascular manifestations. These conditions are classified by classified according to their molecular genetic defects, historically designated as complementation groups (cblA–cblJ), into groups that affect extracellular handling of cobalamin (intrinsic factor deficiency [GIF], Imerslund-Gräsbeck syndrome [CUB, AMN], transcobalamin deficiency [TCN2], transcobalamin receptor deficiency [CD320]) and groups that affect intracellular processing (including cblA, cblB, cblC, cblD, cblE, cblF, cblG, cblJ and related intracellular cobalamin-processing defects, including the most frequent disorder, cblC disease, caused by biallelic variants in MMACHC). Advances in tandem mass-spectrometry newborn screening, rapid genomic sequencing, and parenteral hydroxocobalamin-based protocols have substantially improved outcomes for early-treated infants, while liver transplantation and emerging gene-addition and genome-editing strategies are reshaping management of isolated methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency. This review summarizes the biochemistry, classification, clinical phenotypes, diagnostic strategy, and current and emerging therapies for inherited disorders of cobalamin metabolism.
Keywords: Vitamin B12; Cobalamin metabolism; Inherited metabolic disorders; Methylmalonic acidemia; cblC disease; MMACHC; Hydroxocobalamin; Newborn screening
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