By Helen Janneson Bense
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. COMT mutations can result in higher levels of circulating dopamine. A1298C mutation can mask a COMT mutation.
Decreased production of glutathione, a major antioxidant required for removing heavy metals from the body.
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. Quinonlic acid is also associated with flu like symptoms such as achy muscles and increased sensitivity to light/sound. A result of viral inflammation, it stimulates NMDA receptors of glutamatergic neurons in the brains and is responsible for the excess production of glutamate. In the presence of mitochondrial dysfunction and subsequent low ATP, there will be an increase in conversion of glutamate to ammonia and alpha ketogluturate with a net loss of NADH. This places even more pressure on BH4 to remove ammonia.
Certain biomarkers can be seen on multiple tests that may give some information to the expression of this gene and severity. Below is a collection of my observations from evaluating numerous test results of those with MTHFR A1298C.
Organic Acid Test - high cis aconitate, citrate and iso citrate all indicate high ammonia levels. High quinolinic acid levels and high Quinolinic acid/Kynurenate ratio indicate microglial activation.
Plasma Amino Acid Test - high arginine and citrulline indicate high ammonia levels. High phenylalanine:tyrosine ratio indicates issues in conversion of phenylalanine to tyrosine. BH4 is needed as a cofactor for the enzyme phenylalanine hydroxylase required for this conversion.
Blood - high RBC folate.
Hair - high aluminium.
Chronic Fatigue Syndrome/ME
Multiple Chemical Sensitivity (MCS)
Autism Spectrum Disorders
Hypersensitivity reactions eg. red ears (due to mast cell degranulation and subsequent high histamine levels)
IBS, IBD, peptic ulcers, increased susceptibility to parasitic infections, low gut butyrate
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).
Support Ammonia detoxification
Antioxidant support to reduce peroxynitrite and superoxide
Increase BH4 production
Considerations for Nutritional Bypasses
Ascorbic acid (Vitamin C) neutralizes Superoxide. Ribose, Inosine and NADH neutralize peroxynitrite.
OPC’s – oligomeric proanthocyanidins, Pycnogenol – anti-oxidants neutralize peroxynitrite and superoxide and regulate 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.
Ammonia control – ammonia RNA, glutamine, NADH, weekly charcoal/mag citrate flushes, Yucca, arabinogalactans, sodium/potassium butyrate.
NADH is a cofactor for DHPR, the enzyme responsible for conversion of BH2 to BH4. This enzyme is inhibited by Aluminium, Lead and A1298C. NADH along with vitamin C also recycle glutathione. NADH is best taken as a sublingual preparation first thing in the morning on an empty stomach.
Neurotransmitter support – Serotonin support includes tryptophan, 5HTP, P5P and B3. Dopamine support includes vitamin D, tyrosine, ginkgo biloba and macuna puriens.
GABA is also important to take to counter glutamate levels. I suggest a sublingual preparation. If you have either MAO A or COMT mutations then be careful when using tryptophan, 5HTP, ginkgo biloba and macuna puriens.
BH4 support – BH4, 5MTHF, NADH, Royal Jelly, Lithium Orotate. Both lithium and 5MTHF will open up the long route of methylation. See more on this below. Always check lithium levels on hair tests before using.
Methyl, adenosyl or hydroxycobalamin (depends on COMT/VDRtaq SNPs as to which B12 form will suit) to be introduced prior to 5MTHF supplementation to prevent methyl trapping.
5MTHF (activated folic acid) neutralizes peroxynitrite and is a cofactor for BH4 production. 5MTHF will open up the long route of methylation and can bring upon a lot of detoxification symptoms if taken too early on in treatment. The whole methylation cycle must be looked at first, and a step by step process is essential before supplementation with 5MTHF is advised. It's best to start with gastrointestinal issues, infections and inflammation, ammonia/glutamate/free radical support, transsulfuration support, mitochondrial support, short route support (BHMT) and then move onto long route support with 5MTHF, B12 and lithium to open the long route of methylation. 5MTHF is a methyl donor and may suit everyone. It will depend on your methyl tolerance which can be determined by your COMT/VDRtaq SNPs.
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... 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;
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 A1298CMTHFR Mutations,
6. Yasko, A., Genetic Bypass, Matrix Press, 2005
7. Robert, J., Return to Autism Page, http://www.heartfixer.com/A....
8. Pall, M., Nitric Oxide, Superoxide & Peroxynitrite,
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