Vitamin B12-responsive methylmalonic acidemia, type cblDv2

Vitamin B12-responsive methylmalonic acidemia, type cblDv2 (also known as cobalamin D deficiency, variant 2, or cblD variant 2) is an extremely rare inherited disorder of intracellular cobalamin (vitamin B12) metabolism. It is caused by mutations in the MMADHC gene (also known as C2orf25), which encodes a protein involved in the intracellular processing and trafficking of cobalamin. In the cblDv2 variant, the defect specifically impairs the synthesis of adenosylcobalamin, the cofactor required by the mitochondrial enzyme methylmalonyl-CoA mutase, while the synthesis of methylcobalamin (needed for methionine synthase) is preserved. This distinguishes cblDv2 from other cblD complementation group variants (cblDv1, which affects methylcobalamin synthesis, and combined cblD, which affects both pathways). The condition primarily affects metabolic pathways in the body, leading to the accumulation of methylmalonic acid in blood and urine (methylmalonic aciduria). Clinical features can include metabolic acidosis, developmental delay, failure to thrive, lethargy, and potentially life-threatening metabolic crises, particularly during periods of illness or metabolic stress. The severity can vary among affected individuals. Because the enzymatic defect is responsive to vitamin B12 supplementation, treatment typically involves pharmacological doses of hydroxocobalamin or cyanocobalamin, which can significantly reduce methylmalonic acid levels and improve clinical outcomes. Dietary protein restriction and carnitine supplementation may also be employed as part of the management strategy. Early diagnosis through newborn screening or clinical suspicion and prompt initiation of treatment are important for optimizing long-term outcomes.

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