A1298C
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Published: Saturday, 28 May 2016 13:15
MTHFR A1298C Polymorphism A1298C single nucleotide polymorphism (SNP) affects the enzyme known as 5,10 MethyleneTetraHydroFolate Reductase (MTHFR). This polymorphism involves a down regulation of the MTHFR enzyme, responsible for the backwards reaction of the folate cycle, where 5-methylfolate (5MTHF) is converted into tetrahydrofolate (THF). This reaction is most important for the production of BH4 – tetrahydrobiopterin. Each turn of the folate cycle and conversion of 5MTHF to THF produces 1 molecule of BH4. In heterozygous and homozygous states, enzyme activity will be compromised by approximately 30% and 70% respectively.
Functions of BH4
• Cofactor for all three isotypes of nitric oxide synthases (nNOS, eNOS, iNOS). NOS is essential for the conversion of arginine to Nitric Oxide (NO) and Citrulline in the Urea Cycle. 2 BH4 molecules are required to drive the Urea Cycle efficiently and produce Citrulline and NO. 1 BH4 molecule will result in the generation of peroxynitrite, and no BH4 results in superoxide formation.
• Detoxification of ammonia – BH4 is required to convert ammonia to urea in the Urea cycle. This is a priority function of BH4.
• BH4 is the rate limiting factor in the production of neurotransmitters – Indolamines: Serotonin and Melatonin; and Catecholamines: Dopamine, Noradrenalin, Adrenalin. BH4 activates enzymes tyrosine hydroxylase and tryptophan hydroxylase in the synthesis of these monoamines. When BH4 is limited in supply these enzymes cannot bind to their amino acid substrates, tyrosine and tryptophan, which are the precursors for these monoamines.
• Cofactor for Phenylalanine hydroxylase in the conversion of Phenylalanine to tyrosine. Consequences of Low BH4
• High levels of ammonia – exacerbated by CBS/NOS SNPs. • High levels reactive oxygen species – superoxide. High levels of reactive nitrogen species – peroxynitrite. These dangerous free radicals trigger microglial activation, increased NMDA receptor stimulation, excessive glutamate production and eventually neuronal degeneration.
• Low levels of all monoamines – depending on COMT/VDRtaq SNPs.
• Decreased production of glutathione.
• High Phenylalanine levels result in low serotonin and GABA.
• When BH4 supply is limited the body will prioritize detoxification of excess ammonia above production of neurotransmitters.
• Excessive production of excitotoxins – glutamate, quinolinic acid and arachidonic acid. Quinolinic acid is associated with higher incidence of seizures.
Associated Conditions
• Chronic Fatigue Syndrome/ME
• Fibromyalgia
• Multiple Chemical Sensitivity (MCS)
• Insomnia
• Depression
• Autism Spectrum Disorders
• Neuro-immune disorders
• Raynaud’s
• Migraine
• Seizures
• Parkinson’s disease
• IBS, IBD, peptic ulcers, increased susceptibility to parasitic infections, low gut butyrate
• Anxiety/Panic disorder
• Ammonia toxicity symptoms – brain fog, spacy, language issues, fatigue, poor concentration, dark circles under eyes, poor learning/memory, headaches, stimulating behaviours, food intolerances (especially protein).
Treatment Aims
1. Support Ammonia detoxification
2. Antioxidant support to reduce peroxynitrite and superoxide
3. Increase BH4 production
4. Neurotransmitter Support Considerations for Nutritional Bypasses
• Ascorbic acid (Vitamin C) neutralizes Superoxide.
• 5MTHF (activated folic acid) neutralizes peroxynitrite and is a cofactor for BH4 production.
• BH4 support – BH4, 5MTHF, NADH, Royal Jelly, Lithium Orotate.
• Hydroxycobalamin – reduces NO.
• NADH is a cofactor for DHPR, the enzyme responsible for conversion of BH2 to BH4. This enzyme is inhibited by Aluminium, Lead and A1298C.
• Ammonia control – glutamine, NADH, weekly charcoal/mag citrate flushes, Yucca, arabinogalactans, sodium/potassium butyrate.
• Neurotransmitter support – tryptophan, 5HTP, tyrosine, ginkgo biloba, P5P, B3.
• Methyl or hydroxycobalamin (depends on COMT/VDRtaq SNPs) to be introduced prior to 5MTHF supplementation to prevent methyl trapping.
• OPC’s – oligomeric proanthocyanidins – anti-oxidant, neutralizes peroxynitrite and superoxide, regulates glutamate:GABA.
Neutralizing free radical production will prevent ongoing microglial activation, NMDA receptor stimulation and subsequent excessive production of excitotoxins like glutamate. Clearing high levels of ammonia from the body will surely make the patient feel better relatively quickly, and will also remove some of the strain on BH4’s role in clearing ammonia. The more BH4 is available for neurotransmitter production, the better the patient will feel in the long run.
References 1. Stahl, S., L-Methylfolate: A Vitamin for Your Monoamines, Journal of Clinical Psychiatry, 69:9, September 2008. 2. Blaylock, R., Microglial Activation and Neurodegeneration, http://web.me.com/dblaylock/Site/Home.html Viewed 21.5.12 3. Erbe, Richard W et al. Severe Methylenetetrahydrofolate Reductase Deficiency, Methionine Synthase, and Nitrous Oxide—A Cautionary Tale. New England Journal of Medicine. July 3, 2003; 349(1):4-6. 4. Gramsbergen, Jan Bert et al. Glutathione depletion in nigrostriatal slice cultures: GABA loss, dopamine resistance and protection by the tetrahydrobiopterin precursor sepiapterin. Brain Research. May 10, 2002; 935:47-58. 5. Lynch, B., MTHFR A1298C Mutation: Some Information on A1298C MTHFR Mutations, http://mthfr.net/mthfr-a1298c-mutation-someinformation- on-a1298c-mthfr-mutations/2011/11/30/ Viewed 21.5.12 6. Yasko, A., Genetic Bypass, Matrix Press, 2005 7. Robert, J., Return to Autism Page, http://www.heartfixer.com/AMRINutrigenomics. htm#MTHFR%20A1298C:%20%205,10- MethyleneTetraHydroFolate%20Reductase%20(%DE%20BH4) Viewed 21.5.12 8. Pall, M., Nitric Oxide, Superoxide & Peroxynitrite, http://www.medicalinsider.com/cardiac3.html viewed 21.5.12
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