MTHFR deficiency (WP4288)

There are currently three hypothesis for demyelination in the Central Nervous System (CNS) of methylenetetrahydrofolate reductase (MTHFR) deficient patients. These three possible mechanisms are: inadequate methionine synthesis, a deficiency of S-adenosylmethionine or accumulation of toxic intermediates from the elevated levels of homocysteine. This pathway includes all three of these possible mechanisms. This pathway was inspired by Chapter 10 of the book of Blau(ISBN 3642403360 (978-3642403361)) and the paper by Prasad et al. (2011, For an overview of disorders related to folate metabolism and transport, please see [].
last edited


Jessev1993, DeSl, Egonw, Khanspers, IreneHemel, Josienlandman, MaintBot, and Fehrhart

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Homo sapiens


Diseases Inborn Errors of Metabolism (IEM) Pathways Rare Diseases


Cell Type Ontology: oligodendrocyte

Pathway Ontology: S-adenosylmethionine homeostasis pathway disease pathway hyperhomocysteinemia pathway folate metabolic pathway methylenetetrahydrofolate reductase deficiency pathway

Disease Ontology: inherited metabolic disorder


Label Type Compact Identifier
Choline Metabolite chebi:15354
Myelin components Pathway wikipathways:WP4304
SAM Metabolite chebi:67040
EHMT1 GeneProduct ensembl:ENSG00000181090
Homocysteine thiolactone Metabolite hmdb:HMDB0002287
MTHFR GeneProduct ensembl:ENSG00000177000
Cytochrome c Protein uniprot:G4XXL9
phosphatidylcholine Metabolite chebi:49183
CASP3 GeneProduct ensembl:ENSG00000164305
[Myelin basic protein]-N-methylarginine Metabolite chebi:10167
Dimethylglycine Metabolite chebi:17724
Homocysteine Metabolite chebi:58199
NMDA 2D Protein uniprot:O15399
[Myelin basic protein]-arginine Metabolite chebi:10166
HNMT Protein uniprot:P50135
Phosphocholine Metabolite chebi:295975
Ca2+ Metabolite chebi:29108
Ceramide Metabolite chebi:17761
Methionine Metabolite chebi:57844
CDP-choline Metabolite chebi:58779
NMDA 1 Protein uniprot:Q05586
NMDA 2A Protein uniprot:F5GZ52
BHMT Protein uniprot:Q93088
Choline kinase alpha Protein uniprot:P35790
DNMT3A GeneProduct ensembl:ENSG00000119772
Betaine aldehyde Metabolite chebi:15710
betaine Metabolite chebi:17750
CHDH Protein uniprot:Q8NE62
5,10-Methylene-THF Metabolite chebi:1989
DNMT3B GeneProduct ensembl:ENSG00000088305
DAG Metabolite chebi:18035
PEMT Protein uniprot:Q9UBM1
PRMT Protein uniprot:B4E0W7
Apoptosis Pathway wikipathways:WP254
sphingomyelin Metabolite chebi:62490
5-Methyl-THF Metabolite chebi:15641
CASP9 GeneProduct ensembl:ENSG00000132906
SAH Metabolite chebi:16680
Oxidative Damage Pathway wikipathways:WP3941
ASMT GeneProduct ensembl:ENSG00000196433
phosphatidylethanolamine Metabolite chebi:16038
Folate metabolism and related disorders Pathway wikipathways:WP4259
reactive oxygen species Metabolite wikidata:Q424361
SGMS 1 Protein uniprot:D3DWC4
MetRS Protein uniprot:P56192
EHMT2 GeneProduct ensembl:ENSG00000204371
COMT GeneProduct ensembl:ENSG00000093010
BADH Protein uniprot:P49419
betaine Metabolite chebi:17750
Choline Metabolite chebi:15354
CHPT-1 Protein uniprot:Q8WUD6
CCT-alpha Protein uniprot:P49585
SAM Metabolite chebi:67040
SAM Metabolite chebi:67040
SAM Metabolite chebi:67040
Homocysteine Metabolite chebi:17230
Homocysteine Metabolite chebi:17230
Ca2+ Metabolite chebi:29108
Homocysteine Metabolite chebi:17230
Cytochrome c Protein uniprot:G4XXL9
Ca2+ Metabolite chebi:29108
DNMT1 GeneProduct ensembl:ENSG00000130816
EC Protein eccode:
EC Protein eccode:


  1. James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA. Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr. 2002 Aug;132(8 Suppl):2361S-2366S. PubMed Europe PMC Scholia
  2. Pajares MA, Pérez-Sala D. Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cell Mol Life Sci. 2006 Dec;63(23):2792–803. PubMed Europe PMC Scholia
  3. Li Z, Vance DE. Phosphatidylcholine and choline homeostasis. J Lipid Res. 2008 Jun;49(6):1187–94. PubMed Europe PMC Scholia
  4. Ueland PM. Choline and betaine in health and disease. J Inherit Metab Dis. 2011 Feb;34(1):3–15. PubMed Europe PMC Scholia
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  6. Prasad AN, Rupar CA, Prasad C. Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Brain Dev. 2011 Oct;33(9):758–69. PubMed Europe PMC Scholia
  7. Poddar R, Paul S. Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. J Neurochem. 2013 Feb;124(4):558–70. PubMed Europe PMC Scholia
  8. Petras M, Tatarkova Z, Kovalska M, Mokra D, Dobrota D, Lehotsky J, et al. Hyperhomocysteinemia as a risk factor for the neuronal system disorders. J Physiol Pharmacol. 2014 Feb;65(1):15–23. PubMed Europe PMC Scholia
  9. Fan X, Jin WY, Wang YT. The NMDA receptor complex: a multifunctional machine at the glutamatergic synapse. Front Cell Neurosci. 2014 Jun 10;8:160. PubMed Europe PMC Scholia
  10. Sharma GS, Singh LR. Conformational status of cytochrome c upon N-homocysteinylation: Implications to cytochrome c release. Arch Biochem Biophys. 2017 Jan 15;614:23–7. PubMed Europe PMC Scholia