Monday, June 4, 2012

MTHFR A1298C Polymorphism

This is an article written by Helen Janneson Bense. She was nice enough to let me share her knowledge. Thank you very much Helen! I greatly appreciate this article. There is so much I need to learn about my specific mutation, A1298C Homozygous. 

Insight Naturopathy is Helen's Facebook page: 

Here is the link to her article:

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

• 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

• 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

• 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.


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, 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 A1298C
MTHFR Mutations,
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,
Viewed 21.5.12

8. Pall, M., Nitric Oxide, Superoxide & Peroxynitrite, viewed 21.5.12

© Insight Naturopathy Helen Janneson Bense 2012


  1. Hello,
    Thank you for your blog. I've just begun reading through it. This first post intrigued me. I am heterozygous for MTHFR C677T and have elevated PAI-1 (89). The symptoms that you describe for ammonia toxicity (brain fog, spacy, language issues, fatigue, poor concentration, poor learning/memory, headaches) describe my main symptoms so perfectly. How could I find out if I have low bh4 and/or ammonia toxicity? is there a test for that? what can you do/take to regulate bh4? Thank you so much for your guidance.

    1. You could possibly have CBS mutations, which also deplete BH4. I tested through I have 4 heterzygous variations of CBS on top of being homoygous for A1298C. I take the precursors for BH4: methylfolate, methylcobalamin, iron, vitamin C and royal jelly. has a list of knowledgeable doctors. I'm working one right now to get my CBS mutations working right.

  2. Hi,
    Great blog! I have been trying to understand all 'this' and your post was helpful in my 'brain fog'. I also Homozygous for A1298C, 1 CBS A13637G (Homo), Homo for 2 SOD2, homo for MAO A R297R, homo for 2 out of 3 NOS2, and homo for VDR Taq/VDR Bsm....Its all so overwhelming to know where to begin. Heal you gut first, right ??