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X-Men Mutant Protocols: A1298C Homozygous

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Jorlev, Feb 26, 2013.

  1. Jorlev

    Jorlev

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    Hello fellow X-Men.

    I have just discovered that I have the MTHFR A1298C homozygous mutation. I've been trying a blend of various protocols found here on Phoenix Rising as well as Dr. Ben Lynch and Dr. Amy Yasko.

    I wanted to start a thread for those who also have this mutation so we might discuss and exchange knowledge specific to it. Tweaks in the protocols that may help; specific supplements that you've found useful; sites with useful studies and the like.

    So far, it appears that those with this mutation may have neurological problems, reduced neurotransmitter production, elevated nitric oxide and peroxinitrite and low BH4 levels.

    Anything insights helpful to those with this mutation would be most appreciated.
    --------------------------------------------------------------------------------------------------------

    I'll get the ball rolling with an interesting presentation I saw from Dr. Yasko regarding the importance of one of the elements depleted by the A1298C mutation: BH4

    In the video she make the following interesting points:

    BH2 to BH4 is inhibited by lead and aluminium.

    Phenylalanine builds up (BH4 needed for conversion to Tyrosine) which inhibits serotonin and GABA production.

    BH4 needed to convert ammonia to urea.

    Need BH4 for NOS (Nitric Oxide Synthase) Dopamine, Epinephrine, Neurepinethrine.

    BH4 needed to make CoQ10

    BH4 - 3 Legged Stool can be hindered by the following:
    CBS Upregulation (depletes BH4 faster for ammonia detox), MTHFR A1298C Mutation (not regenerating BH4)
    Chonic Bacteria infection/ Aluminium (inhibits stabilization)

    5-formylTHF may be needed in addition to 5-methylTHF

    Light Therapy may increase BH4 levels

    Hydrogen Peroxide H2O2 stimulates BH4 levels

    Low Glutathione impares BH4, Dopamine & GABA. Low BH4 increases suseptiblity to toxicity, more sensitive to G depletion in absense of BH4.

    BH4 - Ureas cycle - still works but generates superoxide: oxidative, neural damage & microglial activation.

    BH4 needed for NO: must be balanced.

    Vtamin C increases BH4 levels and NOS levels.

    Royal Jelly: Amino acids and low dose form of BH4

    Hydroxy B12 scavenging NO

    Low BH4 leads to increased peroxynitrite which suppresses mitochonrrial energy production. Interferes with brain function and enhances excitotoxins.

    Low Magnesium enhances excitotoxins.

    Microglyia Activiation: The immune system of the nervous sytem.
    Secretes cytokines, chemokines, eucisaboids, protesase, complement and a least two excitotoxins. cytokines are neurotropic during neurodevelopment but chronic activation can be distructive.

    Spiralina and Apple limits overactivation. Helps recovery
     
  2. dbkita

    dbkita Senior Member

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    Some comments and questions from watching the video:

    1) I had forgotten about the phenyalanine conversion. Then again the people taking prescription BH4 are people with PKU which makes sense. But why does that disrupt serotonin and GABA production. Not clear.

    2) Why are NO levels high? I though BH4 was needed for NOS. I thought without enough BH4 there is a shunt to H2O2 production. No idea why H2O2 stimulates BH4 production btw. Why do we want to scavenge NO? Need to confirm that with some other papers.

    3) Yes low BH4 leads to increased peroxynitrite but the cleanup mechanism involves adb12 ("Gorilla in the Room" thread). Hydroxy b12 is NOT the main pathway for this. Quite frankly I think Dr Yasko is not aware of the recent research on this.

    4) When you say "spirulina and apple limits overactivaton" ... what do you mean? Overactivation of what?

    5) BH4 is also needed for serotonin production, not just catecholamines.

    6) Interesting that BH4 is needed to make COQ10. Did not know that one.

    7) Vitamin C increases BH4 by virtue of BH2 to BH4 cycling which also takes folates. I think Dr Yasko dislikes more than a 200 mcg of L5MTHF so she pushes the folinic acid. There are papers that use folic or folinic acid to stimulate this recycling. I would think L5mthf would work just as well. Anyone have any research to the contrary?

    8) The big missing bullet point is how INFLAMMATION lowers BH4 production. Dr Yasko devotes several slides to this. That could be the primary epigenetic stress for most people with problems in this arena who are not strictly homozygous A1298c.
     
  3. Jorlev

    Jorlev

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    Great page for those with A1298C
    http://survivingmthfr.blogspot.com/2012/06/mthfr-a1298c-polymorphism_04.html

    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:
    http://www.facebook.com/pages/Insight-Naturopathy/226698217365990

    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.
     
    merylg likes this.
  4. dbkita

    dbkita Senior Member

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    That is taken from the Yasko handbook almost verbatim.

    I had forgotten about the lithium connection. The actual mechanism involving MTHFR and BH4 is in dispute. Not everyone buys Yasko's theory on this. I am undecided.

    HB12 is a poor surrogate for lowering peroxynitrites. I think the jury is out if lowering or raising NO is a good or a bad thing dependent on how one deals with peroxynitrites and other nitrogen radicals.

    The link to glutamine and ammonia is also a matter of controversy. Yasko et all typically forbid glutamine. Yet like the author (Helen) I find glutamine to be beneficial. Yucca is promising for my own testing but for some reason induces reflux in me (? not sure?).

    I believe mb12 is superior to hb12 for almost any scenario. If someone has COMT -/- then maybe they just can't stand too high a level of mb12. I have a hard time reconciling hb12 for any reason.

    Again one of the biggest missing elements is inflammation. If bad enough it will trump most of the other measures taken.

    Here it is explained in a lecture: http://vimeo.com/31010898
     
    merylg likes this.
  5. aquariusgirl

    aquariusgirl Senior Member

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    What is the lithium connection? Does lithium up regulate BH4 production?
    Also does anyone know if Supplemental BH4 crosses the BBB?
     
  6. dbkita

    dbkita Senior Member

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    I don't remember off the top of my head but I am pretty sure the video lecture discusses the lithium connection. But again one of my takeaways was the inflammation stress put on the biopterin vs neopterin production which can be huge.

    I think where the jury is still out is if methylfolate truly is a cofactor for production of BH4 or instead about the recycling from BH2 (which is known in the literature). Dr Yasko and others in her court emphatically claim that methylfolate upregulates the primary production path for BH4 but to my knowledge there is no scientific research that conclusively shows this to be the case. Regardless methylfolate will bolster BH4 levels whether by recycling or by indirect mechanisms. I am not arguing with the clinical observations. Just being careful to jump to conclusions on the precise biochemical mechanism.

    And yes it does cross the BBB.

    Here is a research article regarding oral BH4 for PKU patients:
    http://www.biopku.org/pdf/fiege.pdf
     
  7. merylg

    merylg Senior Member

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    Sydney, NSW, Australia
    "Nenad Blau (Switzerland) explained that BH4 can show other beneficial effects beyond Phe level reduction, favoring an increase in neurotransmitters with positive neurological effects. BH4 crosses the blood-brain barrier and seems to improve endothelial function, thus possibly reducing oxidative stress in the brain as well as in the cardiovascular system."

    http://www.seronosymposia.org/en/en...nuria-group-epg-symposium/medical-report.html








     
  8. aquariusgirl

    aquariusgirl Senior Member

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    I think this is why minocycline has been found helpful to schizophrenia patients. Tones down neurological inflammation.
    Has anyone posted that James clellan paper on BH4, lithium, BPD & Schizophrenia on this thread?
    Then there is that new paper that implicated genes that regulate calcium channels in the brain that came out this week . I would link but I am in A rush.

    Unless mistaken , all of it links to inflammation ,excitotoxicity etc...Interesting stuff

    I am wondering if minocycline (or substitute yr anti inflammatory of choice...LDN etc) plus BH4 would be a good protocol?

    Anyone doing that?
     
  9. aquariusgirl

    aquariusgirl Senior Member

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    If u suspect u have a bh4 problem what are the best tests? Phenylalanine? Biopterin?
     
  10. Freddd

    Freddd Senior Member

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    Salt Lake City
    HI Jorlov,

    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).


    Hi Jorlov,

    This looks like an awful lot of overlap to the Deadlock Quartet with the many variations of expression form how all of the parts fit together. And of coursre there is that AdoCbl Gorilla conection. So this mutation then is something that makes us all more susceptable?
     
  11. Jorlev

    Jorlev

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    Can you explain the Deadlock Quartet?
    P.S. It's Jorlev not Jorlov.
     
  12. Jorlev

    Jorlev

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    Hey A1298C Homozygous-ians,

    Obviously, with our BH4 problem we probably have peroxinitrite and ammonia buildup. In fact, I was speaking to a relative recently who said she remembers that as an infant I had to be on a "special diet." which didn't mean much at the the time but I can across info on Hyperphenylalninemia and it's severe form Phenylketonuria which requires a special diet for infants. Trying to get old birth hospital records to confirm.
    http://en.wikipedia.org/wiki/Hyperphenylalaninemia

    Anyway, I also just got results showing low Carnitine, which my Dr said could contribute to my small fiber neuropathy.
    Was wondering if supplementing with Carnitine (LCF, ALC or both) to help my SFN winds up producing more phenylalanine, peroxinitrite and ammonia which damages my small fibers. Or does the buildup of these occur only when meat is consumed and broken down. It may be mostly ammonia i'm referring to. Not sure if meat decomposition results in phenylalalnine or peroxinitrite increase or not.
     
  13. Jorlev

    Jorlev

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    A1298C-ers,
    Wondering how much Methylfolate you're taking. We may not need as much as 677T folks but how much is generally needed to reverse the cycle?
     
  14. dbkita

    dbkita Senior Member

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    I forget how but l-carnitine is critical to lowering ammonia in the urea cycle.
     
  15. parisflower

    parisflower

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    Hello Fellow A1298C'ers,
    I just got my results back from 23andMe and could really use some advice. I've done a fair bit of reading on methylation, but boy, am I in over my head trying to make sense of my results.

    (++)
    MTHFR A1298C
    VDR Taq
    MTRR A66G
    SHMT1 C1420T

    (+/-)
    MAO-A R297R
    CBS C699T

    Does anyone have recommendations for a good consultant to help me interpret my results?
    Thank you!!
     
  16. Jorlev

    Jorlev

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    L-Arginine helps remove ammonia according to Wikipedia.
    http://en.wikipedia.org/wiki/Arginine

    In regards to low BH4 and arginine, I'm not sure if taking arginine inhibits or increases the production of Peroxinitrite.
    From what I've read, BH4 is cofactor for NOS enzyme to product NO from Arginine. In absence of BH4, NOS produces Superoxide which reacts with NO to produce Peroxinitrite. So while I'm sure producing NO is better than producing Superoxide, NO reacting with Superoxide to create Peroxinitrite makes me believe that NO really needs to be in proper balance and is is beneficial and in excess perhaps dangerous.
     
  17. Jorlev

    Jorlev

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    MTHFR Support has a list of practitioners who are knowledgeable regarding methylation. While I'm not sure if the know about all the SNPs, I bet they are more likely to know than your typical MD. I would pick one off the list in your state, contact and ask.
    http://www.mthfrsupport.com/find-a-practitioner.html
     
  18. Jorlev

    Jorlev

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  19. dbkita

    dbkita Senior Member

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    More NO may lead to more peroxynitrite which requires both BH4 AND Adb12. I think limiting arginine to specifically inhibit NO production for fear of peroxynitrite is not the way to go. The solution is to have enough BH4 and adb12 to efficiently process peroxynitrite. The Gorilla in the Room article mentioned several places on these forums shook up my understanding of peroxynitrite removal.

    Both arginine and l-ornithine remove ammonia but of course BH4 is needed to do this as well.
     
  20. dbkita

    dbkita Senior Member

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