Vitamin B<sub>12</sub> deficiency, beyond megaloblastic anemia: the role of alternative pathways for cellular uptake of vitamin B<sub>12</sub>

Vitamin B 12 deficiency (cobalamin [Cbl]) causes megaloblastic anemia with/without neurological alterations.Cbl binds to transcobalamin (TC), giving rise to holotranscobalamin (holoTC), which is taken up by its receptor, TCblR or CD320; this is the canonical uptake pathway for all cells, but there are alternative pathways.Fetuses with congenital disorders of TC and TCblR/CD320 are viable; B 12 uptake is mediated by megalin/LRP2.At birth, its expression decreases markedly and these deficiencies become clinically apparent.However, the TC disorder causes severe hematological and neurological manifestations, while the TCblR/CD320 disorder causes mild symptoms and limited to the nervous system.This difference is attributed to the uptake pathway mediated by the LDLR (low-density lipoprotein receptor), present in all cells except in neurological ones.This function was discovered in the study of autoimmune central vitamin B 12 deficiency, as these patients present anti-TCbl/CD320 autoantibodies and neurological symptoms without hematological ones.All three are receptors of the LDLR family, and their involvement in the cellular uptake of vitamin B 12 opens new perspectives related to neurological symptoms or thrombosis.Finally, the holoTC-TCblR/CD320 uptake pathway is implicated in multiple sclerosis and in the uptake of drugs active against this disease, where Cbl plays an anti-neuroinflammatory role.