Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

Nutritional deficiency and genetic errors that impair the transport, absorption, and utilization of vitamin B(12) (B(12)) lead to hematological and neurological manifestations. The cblC disease (cobalamin complementation type C) is an autosomal recessive disorder caused by mutations and epi-mutations in the MMACHC gene and the most common inborn error of B(12) metabolism. Pathogenic mutations in MMACHC disrupt enzymatic processing of B(12), an indispensable step before micronutrient utilization by the two B(12)-dependent enzymes methionine synthase (MS) and methylmalonyl-CoA mutase (MUT). As a result, patients with cblC disease exhibit plasma elevation of homocysteine (Hcy, substrate of MS) and methylmalonic acid (MMA, degradation product of methylmalonyl-CoA, substrate of MUT). The cblC disorder manifests early in childhood or in late adulthood with heterogeneous multi-organ involvement. This review covers current knowledge on the cblC disease, structure–function relationships of the MMACHC protein, the genotypic and phenotypic spectra in humans, experimental disease models, and promising therapies.