Inherited disorders of cobalamin metabolism in childhood: biochemical and clinical perspectives

Cobalamin (vitamin B12) is a vitamin with a defined role in human metabolism. Since its discovery in the 20th century, our understanding of its deficiency that results in multifaceted disorders with a significant impact on neurological health has evolved. While classically associated with megaloblastic anemia, its neurological manifestations can be diverse, severe, and often precede hematological changes. This review provides a detailed analysis of the role of cobalamin in different biochemical pathways, clinical syndromes, underlying pathophysiological mechanisms, and inborn errors of metabolism associated with genetic defects in the pediatric population. The primary neurological insult is related to demyelination and axonal loss in both the central and peripheral nervous systems, leading to a spectrum of symptoms from peripheral neuropathy to severe myelopathy and neuropsychiatric decline. The metabolic networks involve critical biochemical pathways affecting the methionine-homocysteine cycle, folate biosynthesis, and energy and lipid metabolism. The genetic basis of these disorders is defined by distinct complementation groups and the genetic mutations identified by molecular genetic testing. The clinical aspects often present with unique profiles and require specialized diagnostic approaches. A nuanced diagnostic strategy that includes measurement of methylmalonic acid and homocysteine is essential, as is prompt and aggressive parenteral treatment to prevent irreversible neurological damage.