The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

J Inherit Metab Dis. 2019 Jul;42(4):686-705. doi: 10.1002/jimd.12012. Epub 2019 Feb 13.


This review gives an overview of clinical characteristics, treatment and outcome of nutritional and acquired cobalamin (Cbl; synonym: vitamin B12) deficiencies, inborn errors of Cbl absorption and intracellular trafficking, as well as methylenetetrahydrofolate dehydrogenase (MTHFD1) and methylene tetrahydrofolate reductase (MTHFR) deficiencies, which impair Cbl-dependent remethylation. Acquired and inborn Cbl-related disorders and MTHFR deficiency cause multisystem, often severe disease. Failure to thrive, neurocognitive or psychiatric symptoms, eye disease, bone marrow alterations, microangiopathy and thromboembolic events are characteristic. The recently identified MTHFD1 defect additionally presents with severe immune deficiency. Deficient Cbl-dependent enzymes cause reduced methylation capacity and metabolite toxicity. Further net-effects of perturbed Cbl function or reduced Cbl supply causing oxidative stress, altered cytokine regulation or immune functions are discussed.

Keywords: Imerslund-Gräsbeck; cobalamin; folate; intrinsic factor; transcobalamin; vitamin B12.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Folic Acid / metabolism
  • Folic Acid Deficiency / etiology*
  • Folic Acid Deficiency / genetics
  • Homocystinuria / etiology*
  • Homocystinuria / genetics
  • Humans
  • Infant, Newborn
  • Metabolic Networks and Pathways
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Muscle Spasticity / etiology*
  • Muscle Spasticity / genetics
  • Psychotic Disorders / etiology
  • Psychotic Disorders / genetics
  • Vitamin B 12 / metabolism
  • Vitamin B 12 Deficiency / etiology*
  • Vitamin B 12 Deficiency / genetics


  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Vitamin B 12

Supplementary concepts

  • Methylenetetrahydrofolate reductase deficiency