Inherited Disorders of Cobalamin Metabolism: A Practical Guide for the Internist

Abstract

Inherited disorders of cobalamin (vitamin B12) metabolism (IDCM) constitute a clinically heterogeneous group of inborn errors of intermediary metabolism resulting from defects in intestinal absorption, plasma transport, or intracellular processing of this essential cofactor. Long regarded as exclusively pediatric diseases, late-onset and adult-presenting forms — notably late-onset cblC disease (biallelic MMACHC variants) and remethylation cycle disorders — are increasingly recognized in internal medicine. In adults, the clinical spectrum encompasses unexplained neuropsychiatric syndromes, recurrent thromboembolic events, chronic kidney disease, and atypical hematological findings, frequently in the presence of normal serum vitamin B12 concentrations, creating a persistent diagnostic gap. Plasma total homocysteine, often markedly elevated and accompanied by elevation of methylmalonic acid, is the most sensitive initial biochemical marker, enabling localization of the defect prior to confirmation by multigene sequencing. Parenteral hydroxocobalamin, superior to cyanocobalamin for intracellular utilization, combined with betaine and folinic acid (vitamin B9) supplementation, can halt disease progression and partially reverse neurological injury when initiated early. In refractory or cobalamin-unresponsive forms, liver transplantation reduces systemic metabolic burden, while gene and mRNA therapies constitute emerging diseasemodifying strategies.