Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

J Inherit Metab Dis. 2017 Jan;40(1):21-48. doi: 10.1007/s10545-016-9991-4. Epub 2016 Nov 30.


Background: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.

Objective: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.

Data sources: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.

Key recommendations: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.

Publication types

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

MeSH terms

  • Animals
  • Homocysteine / genetics
  • Humans
  • Methionine / genetics
  • Methylation / drug effects*
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency*
  • Proto-Oncogene Proteins c-cbl / deficiency*
  • Vitamin B 12 / pharmacology*
  • Vitamin B 12 / therapeutic use*


  • Homocysteine
  • Methionine
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Proto-Oncogene Proteins c-cbl
  • Vitamin B 12