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MTHFS defect (folinic acid intolerance) - request for genetic data

Discussion in 'Genetic Testing and SNPs' started by nandixon, Sep 3, 2012.

  1. Sroll

    Sroll

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    Hello, I have also bad reaction to folinic acid 800mcg Kirkman Labs. It send me down for 3 days. Pressure in my head, bloodshot eyes, increased inflammation, thyroid swelling...
    Rich=1, nandixon=2, Gestalt=3, Anne=4, caledonia=5, geesiddiqui=6, I.R.Baboon=7, Lynn_M=8, merylg=9 snowathlete=10, roxie60=11, drex13=12, Sea=13, Creekee=14, Paula=15, msinnott=16, Sroll=17

    rs8923 CT (TT) (TT) (TT) (TT) (TT) (TT) (CT) (TT) (TT) (TT) (CT) (TT) (CT) (CT) (CT) (TT)
    rs2733103 CC (CT) (CC) (CT) (CT) (CT) (CT) (CC) (TT) (CC) (CC) (CT) (CC) (CC) (CT) (CC) (CC)
    rs16971427 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA)x (AA) (AA) (AA) (AA) (AA) (AA)
    rs655473 AA (AA) (AA) (AA) (AA) (AG) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA)
    rs17284990 TT (CT) (CT) (TT) (TT) (TT) (TT) (CT) (TT) (TT) (CT) (TT) (TT) (TT) (TT) (TT) (TT)
    rs16971450 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AG) (AG) x (AA) (AA) (AG) (AG) (AA) (AG)
    rs6495446 CT (CC) (CC) (CC) (CC) (CC) (CC) (CT) (CC) (CT)(CT) +++ (CT) (CC) (TT) (CT) (CT) (CT)
    rs7177659 CC (AA) (AA) (AA) (AC) (AA) (AC) (AA) (AA) (CC) (AC)*** (AC) (CC) (AC) (CC) (CC) (AA)
    rs6495449 GG (GG) (GG) (AG) (GG) (GG) (GG) (GG) (GG) (AG) (GG) (GG) (GG) (GG) (GG) (GG) (AG)
    rs17285431 AC (AA) (AA) (AC) (AA) (AA) (AC) (AA) (AA) (AC)(AA) (AC) (AA) (AA) (AA) (AC) (AC)
    rs6495451 CT (CC) (CT) (CT) (CC) (CC) (CT) (CT) (CC) (TT) (CT) (CT) (CC) (TT) (TT) (CT) (TT)
    rs2586154 GG (AG) (AG) (GG) (GG) (AG) (GG) (GG) (GG) (GG) (AG) (GG) (GG) (GG) (GG) (GG) (GG)
    rs12899781 GT (TT) (TT) (GT) (TT) (TT) (GT) (TT) (TT) (GT)(TT) (GT) (TT) (TT) (TT) (GT) (GT)
    rs16971478 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA)x (AA) (AA) (AA) (AG) (AA) (AA)
    rs2586153 CC (CT) (CC) (CT) (CT) (CT) (CC) (CC) (TT) (CC) (CC) (CT) (CC) (CC) (CC) (CC) (CC)
    rs2562744 AA (AC) (CC) (AC) (AA) (AA) (AA) (AC) (AA) (CC)(CC) (AA) (AA) (CC) (CC) (AA) (CC)
    rs2733106 AA (AG) (AA) (AG) (AG) (AG) (AA) (AA) (GG) (AA)(AA) (AG) (AA) (AA) (AA) (AA) (AA)
    rs12438477 CC (CC) (AC) (AC) (CC) (CC) (CC) (AC) (CC) (AA)(AC) (CC) (CC) (AA) (AA) (CC) (AA)
    rs12898642 CT (TT) (CT) (CT) (TT) (TT) (CT) (CT) (TT) (CC)(CT) (CT) (TT) (CC) (CC) (CT) (CC)
    rs2586182 AA (AC) (AC) (AA) (AA) (AA) (AA) (AA) (AA) (AA)(AC) (AA) (AA) (AA) (AA) (AA) (AA)
    rs2733088 AG (AG) (GG) (AG) (AA) (AA) (AG) (AG) (AA) (GG)(GG) (AG) (AA) (GG) (GG) (AG) (GG)
    rs12440798 CC (CC) (CT) (CC) (CC) (CC) (CC) (CT) (CC) (CC)(CC) (CC) (CC) (CT) (CT) (CC) (CT)

    MTHFS 2 4 5 6 7 8 9 10 11 14 15 16 17
    rs685487 (GG) (AG) (AG) (AG) (AG) (AG) (GG) (AA)(AG) (AA) (AG) (AA) (AA)
    rs8033649 (CC) (CC) (CC) (CC) (CC) (CC) (CC) (CC)(CC) (CC) (CC) (CC) (CC)

    My SHMT C1420T rs1979277 is AG

    SHMT 2 RS12319666 GG
    SHMT 2 RS34095989 AG
     
  2. S.A.

    S.A.

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    Missouri
    @Critterina that would be awesome. As I was reading thru posts I was thinking it would be great to have an updated summary. My brother also tested out with the MTHFS +/+. He's always hated green veg. My son doesn't seem to do too bad with green now that he's on methylfolate, but he's on about 1200/day and NutraEval still shows low levels. Also, this is very odd, his methionine is wayyyy too high, which seems to be the opposite of what should happen.
     
  3. Critterina

    Critterina Senior Member

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    Arizona, USA
  4. S.A.

    S.A.

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    Missouri
    Thanks, @Critterina I looked at the document, but I used MTHFRsupport.com and they only report on 1 MTHFS gene mutation. Do you get several more by using one of the other sites?
     
  5. Critterina

    Critterina Senior Member

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    Hi @S.A. , I just went to 23andMe and selected "Browse Raw Data". I don't remember whether I just put in MTHFS (in the left side of the search box) and got all of them, or if I put in each rs number individually (in the right side of the search box). Either way it's pretty easy.
     
    S.A. likes this.
  6. Vegas

    Vegas Senior Member

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    I would think that this data collection would attract more positive than negative responses, for those looking to report MTHFS snps, but perhaps not. Of course it may be valuable nonetheless, depending upon the strength of the associations. I tend to think MTHFS/SHMT is a particularly vulnerable part of the metabolism. Have you been able to draw any conclusions from the collective results?
     
    S.A. likes this.
  7. Critterina

    Critterina Senior Member

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    No, I've not been able to draw results. Partly from the fact that most people who contributed their SNPs didn't report on whether they were folinic acid intolerant. There was also no real criteria for what defines "intolerant".
     
  8. Vegas

    Vegas Senior Member

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    Thank you very much for letting me know. Maybe you could alter the spreadsheet to include a category that at least includes a subjective explanation of symptoms and a yes/no as to if any effect is evident. Looks like many of those participants are still around.
     
    S.A. and Critterina like this.
  9. Critterina

    Critterina Senior Member

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    I'll have to check...there was a column at the top for whether you were intolerant or not, when I did it in Excel. Maybe I lost it when I transferred it to Word. I don't know what the symptoms are. Do you?

    I will check on the intolerance markings that I had. You're free to edit the document. I made it so that anyone with the link could edit it. That way, it can go forward if something should happen to me.
     
    S.A. likes this.
  10. Vegas

    Vegas Senior Member

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    In my estimation, the symptoms would likely relate to those effects which can be attributed to inhibition of SHMT. There is redundancy for glycine synthesis and of course it comes in through the diet, but the more dramatic effects are likely to relate to the effects this could have on the conversion of tetrahydrofolate to 5,10-Methylenetetrahydrofolate. I think this is particularly important in a setting of impaired hydrolysis. A scarcity of this reactant would effectively inhibit both the synthesis of methyltetrahydrofolate as well as the synthesis of thymidine. I think the focus has generally been on the former, based upon the popularization of these SNP's and the effects supplementing this can have, but I think the more consequential part of this reaction may relate to the inhibition of deoxythymidine, which could have pretty broad-based effects including repairing cells and loss of energy.

    If both this denovo synthesis of thymidine was inhibited and nucleotide hydrolysis (the collateral way in which these building blocks of DNA are made available through digestion of nucleic acids) was similarly impaired, the effect of diminished deoxythymidine synthesis via SHMT inefficiency secondary to inhibition by folinic acid, could greatly diminish the high energy phosphate pool. I have an idea that this denovo synthesis and the catabolism of proteins is linked up for a reason.

    So what would it do, cause a loss of energy, in the body, and in the brain. How do I know, because I withheld 5-MTHF for a couple of months and then loaded up with folinic acid, which was one of the worst days of my life. It caused massive depression in minutes.

    On a happier note, :) this is also where Riboflavin and its FAD comes into play, and in my opinion, why B2 becomes essential when people try to play around too much with their biochemistry. Cells can't keep up with the nucleoside turnover and you get things like mouth ulcers. This part of the metabolism wants 5MTHF AND B2. A little glycine may be good too. Of course, this is just my interpretation.
     
  11. Critterina

    Critterina Senior Member

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    So, @Vegas,

    If I read you right, you'd vote for "massive depression" as a sign of folinic acid intolerance, brought on by "loading up", which would be what dosage, approximately. And you'd acknowledge the possibility of body fatigue and brain fatigue as theoretical possibilities.

    I would vote for excessive sleepiness, starting about 15-20 minutes after taking 800mcg, but I'm not sure it is intolerance, as ribose, niacinamide, L-carnitine and Co-Q10 (some element or all?) seemed to relieve it. Or maybe those were just start-up symptoms? Hard to tell.
     
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  12. Vegas

    Vegas Senior Member

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    2400 mg. Yes, I think these are all possible.

    Your excessive sleepiness, I think it would be hard to say whether or not this represented a negative reaction to this reduced form of folate vs. the effects it produced upon being metabolized and available to meet a longstanding deficiency. We would need more data points to draw any conclusions. The effects of Ribose, CoQ-10, carnitine, & Niacinamide may not be all that helpful in understanding what is happening, although, I would say that all were negative for me, at one time when any attempt to override natural processes and stimulate energy generation was met with a negative response. Ribose was by far the most dramatic in its negative effects. In fact it was partly what helped me figure out what was happening. I couldn't recycle energy and the Ribose basically yielded energy as heat. It also stimulated ravenous hunger, which I interpreted as a need for nucleotides based upon the inhibited de novo synthesis. Of course, few would experiences this, you have to almost die.
     
  13. Tunguska

    Tunguska

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  14. nandixon

    nandixon Senior Member

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    I'm pretty sure the arrow (with your red question mark below it) drawn from folinic acid to methylfolate is an inadvertent mistake by the authors. MTHFS is the only enzyme I'm aware of that acts on folinic acid for its transformation to methylfolate.

    Also, the green arrowhead you've drawn indicating that methylfolate can reversibly transform back into methylene-THF is not correct when we're talking about what happens within the human body. The forward reaction (i.e., MTHFR using the cofactors FADH2 and NADPH to transform methylene-THF into methylfolate) is irreversible under physiological conditions.

    On the other hand, MTHFR can be made to run in reverse in vitro. For example, the artificial electron acceptor menadione is often used to assay the enzyme in the reverse direction. (And as mentioned on the other thread, quinoid-BH2 can apparently be used similarly to menadione to run MTHFR in the reverse direction as well - in vitro).
     
    Last edited: Dec 3, 2014
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  15. Tunguska

    Tunguska

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    Thanks, it seemed oddly unreferenced but who am I to doubt the british journal of cancer.

    Corrected for the sake of completeness.
    [​IMG]
     

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