MTHFR deficiency (WP4288)

Homo sapiens

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 [].


Jesse Vercoulen , Denise Slenter , Egon Willighagen , Kristina Hanspers , Irene Hemel , Josien Landman , Friederike Ehrhart , and Eric Weitz


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Homo sapiens


Diseases Inherited Metabolic Disorders (IMD) Pathways Rare Diseases


Pathway Ontology

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

Cell Type Ontology


Disease Ontology

inherited metabolic disorder


Label Type Compact URI Comment
Choline Metabolite chebi:15354 Methionine Hypothesis
SAM Metabolite chebi:67040 SAMdef Hypothesis
Homocysteine thiolactone Metabolite hmdb:HMDB0002287 Toxic Hypothesis
Phosphatidylcholine Metabolite chebi:49183 Methionine Hypothesis
[Myelin basic protein]-N-methylarginine Metabolite chebi:10167 SAMdef Hypothesis
Dimethylglycine Metabolite chebi:17724
Homocysteine Metabolite chebi:58199
[Myelin basic protein]-arginine Metabolite chebi:10166 SAMdef Hypothesis
Phosphocholine Metabolite chebi:295975 Methionine Hypothesis
Ca2+ Metabolite chebi:29108 Toxic Hypothesis
Ceramide Metabolite chebi:17761 Methionine Hypothesis
Methionine Metabolite chebi:57844
CDP-choline Metabolite chebi:58779 Methionine Hypothesis
Betaine aldehyde Metabolite chebi:15710 Methionine Hypothesis
betaine Metabolite chebi:17750
5,10-Methylene-THF Metabolite chebi:1989
DAG Metabolite chebi:18035 Methionine Hypothesis
Sphingomyelin Metabolite chebi:64583 Methionine Hypothesis
5-Methyl-THF Metabolite chebi:15641
SAH Metabolite chebi:16680 SAMdef Hypothesis
Phosphatidylethanolamine Metabolite chebi:16038 Methionine Hypothesis
Reactive oxygen species Metabolite wikidata:Q424361 Toxic Hypothesis
Betaine Metabolite chebi:17750 Methionine Hypothesis
Choline Metabolite chebi:15354 Methionine Hypothesis
SAM Metabolite chebi:67040 Methionine Hypothesis
SAM Metabolite chebi:67040 Methionine Hypothesis
SAM Metabolite chebi:67040 Methionine Hypothesis
Homocysteine Metabolite chebi:17230 Toxic Hypothesis
Homocysteine Metabolite chebi:17230 Toxic Hypothesis
Ca2+ Metabolite chebi:29108 Toxic Hypothesis
Homocysteine Metabolite chebi:17230 Toxic Hypothesis
Ca2+ Metabolite chebi:29108 Toxic Hypothesis
EHMT1 GeneProduct ensembl:ENSG00000181090 SAMdef Hypothesis
MTHFR GeneProduct ensembl:ENSG00000177000
CASP3 GeneProduct ensembl:ENSG00000164305 Toxic Hypothesis
DNMT3A GeneProduct ensembl:ENSG00000119772 SAMdef Hypothesis
DNMT3B GeneProduct ensembl:ENSG00000088305 SAMdef Hypothesis
CASP9 GeneProduct ensembl:ENSG00000132906 Toxic Hypothesis
ASMT GeneProduct ensembl:ENSG00000196433 SAMdef Hypothesis
EHMT2 GeneProduct ensembl:ENSG00000204371
COMT GeneProduct ensembl:ENSG00000093010 SAMdef Hypothesis
DNMT1 GeneProduct ensembl:ENSG00000130816 SAMdef Hypothesis
Cytochrome c Protein uniprot:G4XXL9 Toxic Hypothesis
NMDA 2D Protein uniprot:O15399 Toxic Hypothesis
HNMT Protein uniprot:P50135
NMDA 1 Protein uniprot:Q05586 Toxic Hypothesis
NMDA 2A Protein uniprot:F5GZ52 Toxic Hypothesis
BHMT Protein uniprot:Q93088
Choline kinase alpha Protein uniprot:P35790 Methionine Hypothesis
CHDH Protein uniprot:Q8NE62 Methionine Hypothesis
PEMT Protein uniprot:Q9UBM1 Methionine Hypothesis
PRMT Protein uniprot:B4E0W7 SAMdef Hypothesis
SGMS 1 Protein uniprot:D3DWC4 Methionine Hypothesis
MetRS Protein uniprot:P56192 Needs annotation
Toxic Hypothesis
BADH Protein uniprot:P49419 Methionine Hypothesis
CHPT-1 Protein uniprot:Q8WUD6 Methionine Hypothesis
CCT-alpha Protein uniprot:P49585 Methionine Hypothesis
Cytochrome c Protein uniprot:G4XXL9 Toxic Hypothesis
EC Protein eccode:
EC Protein eccode:


  1. Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA. J Nutr. 2002 Aug;132(8 Suppl):2361S-2366S. PubMed Europe PMC Scholia
  2. Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Pajares MA, Pérez-Sala D. Cell Mol Life Sci. 2006 Dec;63(23):2792–803. PubMed Europe PMC Scholia
  3. Phosphatidylcholine and choline homeostasis. Li Z, Vance DE. J Lipid Res. 2008 Jun;49(6):1187–94. PubMed Europe PMC Scholia
  4. Choline and betaine in health and disease. Ueland PM. J Inherit Metab Dis. 2011 Feb;34(1):3–15. PubMed Europe PMC Scholia
  5. An overview of sphingolipid metabolism: from synthesis to breakdown. Gault CR, Obeid LM, Hannun YA. Adv Exp Med Biol. 2010;688:1–23. PubMed Europe PMC Scholia
  6. Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Prasad AN, Rupar CA, Prasad C. Brain Dev. 2011 Oct;33(9):758–69. PubMed Europe PMC Scholia
  7. Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. Poddar R, Paul S. J Neurochem. 2013 Feb;124(4):558–70. PubMed Europe PMC Scholia
  8. Hyperhomocysteinemia as a risk factor for the neuronal system disorders. Petras M, Tatarkova Z, Kovalska M, Mokra D, Dobrota D, Lehotsky J, et al. J Physiol Pharmacol. 2014 Feb;65(1):15–23. PubMed Europe PMC Scholia
  9. The NMDA receptor complex: a multifunctional machine at the glutamatergic synapse. Fan X, Jin WY, Wang YT. Front Cell Neurosci. 2014 Jun 10;8:160. PubMed Europe PMC Scholia
  10. Conformational status of cytochrome c upon N-homocysteinylation: Implications to cytochrome c release. Sharma GS, Singh LR. Arch Biochem Biophys. 2017 Jan 15;614:23–7. PubMed Europe PMC Scholia