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 B₁₂ (B₁₂) 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 B₁₂ metabolism. Pathogenic mutations in MMACHC disrupt enzymatic processing of B₁₂, an indispensable step before micronutrient utilization by the two B₁₂-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.