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](https://www.ncbi.nlm.nih.gov/pubmed/21778025). For an overview of disorders related to folate metabolism and transport, please see [WP4259](https://www.wikipathways.org/index.php/Pathway:WP4259). fae Methionine Hypothesis SAMdef Hypothesis SAMdef Hypothesis Toxic Hypothesis Toxic Hypothesis Methionine Hypothesis Toxic Hypothesis SAMdef Hypothesis Toxic Hypothesis SAMdef Hypothesis Methionine Hypothesis Toxic Hypothesis Methionine Hypothesis Methionine Hypothesis Toxic Hypothesis Toxic Hypothesis Methionine Hypothesis SAMdef Hypothesis Methionine Hypothesis Methionine Hypothesis SAMdef Hypothesis Methionine Hypothesis Methionine Hypothesis SAMdef Hypothesis Methionine Hypothesis Toxic Hypothesis SAMdef Hypothesis SAMdef Hypothesis Methionine Hypothesis Toxic Hypothesis Methionine Hypothesis Needs annotation Toxic Hypothesis SAMdef Hypothesis Methionine Hypothesis Methionine Hypothesis Methionine Hypothesis Methionine Hypothesis Methionine Hypothesis Methionine Hypothesis Methionine Hypothesis Methionine Hypothesis Toxic Hypothesis Toxic Hypothesis Toxic Hypothesis Toxic Hypothesis Toxic Hypothesis Toxic Hypothesis SAMdef Hypothesis c18 Protein homocysteinylation Auto-oxidation c18 c18 f46 Influx of calcium e47 c18 e4d a04 e47 e4d SAH acts as a competetive inhibitor for several proteins. Mitochrondrial dysfunction Inadequate methionine synthesis Influx of calcium Auto-oxidation ade SAM is decreased in MTHFR deficiency Cytochrome C release Deficiency of S-adenosylmethionine Protein homocysteinylation a04 MBP methylation is decreased in MTHFR deficiency MBP is a component of myelin sheat. Methylation is needed for structure stability. Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and are overactivated. bd9 a9a bd9 fc0 18204095 PubMed Phosphatidylcholine and choline homeostasis. J Lipid Res 2008 18204095 PubMed Phosphatidylcholine and choline homeostasis. J Lipid Res 2008 Li Z Vance DE 28003096 PubMed Conformational status of cytochrome c upon N-homocysteinylation: Implications to cytochrome c release. Arch Biochem Biophys 2017 Sharma GS Singh LR 24622826 PubMed Hyperhomocysteinemia as a risk factor for the neuronal system disorders. J Physiol Pharmacol 2014 Petras M Tatarkova Z Kovalska M Mokra D Dobrota D Lehotsky J Drgova A 24959120 PubMed The NMDA receptor complex: a multifunctional machine at the glutamatergic synapse. Front Cell Neurosci 2014 Fan X Jin WY Wang YT 20919643 PubMed An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 2010 Gault CR Obeid LM Hannun YA inherited metabolic disorder DOID:655 Disease folate metabolic pathway PW:0000140 Pathway Ontology S-adenosylmethionine homeostasis pathway PW:0001693 Pathway Ontology oligodendrocyte CL:0000128 Cell Type 20446114 PubMed Choline and betaine in health and disease. J Inherit Metab Dis 2011 Ueland PM methylenetetrahydrofolate reductase deficiency pathway PW:0002343 Pathway Ontology 12163693 PubMed Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr 2002 James SJ Melnyk S Pogribna M Pogribny IP Caudill MA 23176034 PubMed Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. J Neurochem 2013 Poddar R Paul S hyperhomocysteinemia disease pathway PW:0001840 Pathway Ontology disease pathway PW:0000013 Pathway Ontology 17086380 PubMed Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cell Mol Life Sci 2006 Pajares MA Perez-Sala D 21778025 PubMed Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Brain Dev 2011 Prasad AN Rupar CA Prasad C