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Over-driving the methylation cycle

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Gestalt, Jun 10, 2012.

  1. Gestalt

    Gestalt Senior Member

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    I have seen Rich mention this as a concern, however I would like to examine this a bit more closely. My primary issue here is with the seemingly incredible low dose of methylfolate on the Simplified Methylation Protocol. 400-800 micro grams of folate as according to RDA. But my question is since when does anyone take RDA of anything in order to get better!? When someone is sick do you recommend 60mg of VitC because that's what the RDA says?

    My understanding is that RDA is one of those antiquated protocols that was based on the absolute bare minimum required of a specific nutrient to not come down with something like scurvy. And on top of that when the protocol was created back in the 60's nutrients from food were considerably more abundant due to less over-farming and less pesticide/herbicide use.

    Other ND's such as Jared M.Skowron are giving child patients 10mg a day of methylfolate and having incredible results within days of administering! (source)

    "A complete lack of dietary folate takes months before deficiency develops as normal individuals have about 500–20,000 µg of folate in body stores." (source - http://en.wikipedia.org/wiki/Folate)

    If normal people can store folate of up to 20mg then and their reserves are constantly being topped off via diet, then yes it is reasonable to understand why RDA of folate might be so low.

    But now we must consider mutations on the MTHFr gene and prevalence. It doesn't matter how much folate your body stores or you get in your diet if you have a down regulation of 5-MTHF production.

    According to Dr.Ben Lynch in regards to mutations on MTHFR C677T
    1 SNP = 40% loss of function
    2 SNPs = 70% loss of function
    (source - http://www.seekinghealth.com/media/Improving-Patient-Outcomes-short-ver.pdf)

    What's more according to statistics about 40% of people globally have an SNP on C677T. With 15% of the people having two variants, resulting in 70% loss of function. Now what is the estimated global rate of CFS/ME? Might there be a correlation?

    I would venture to guess yes. Most...80%+ of people with ME/CFS probably have at least 1 if not 2 SNP's on the very gene that codes for the enzyme that creates methylfolate. This is why I believe gene testing is so important. And also why in most cases PWME need to have much higher doses of methyfolate than the RDA...

    Looking a the the following results seems to prove my point.
    mthf.jpg
    5-MTHF levels barely moved! You could stick people on the RDA of methylfolate for years, and because of the mutaitons on the C677T gene and lack of controvertible stores, people will be chronically low and undernourished with methyfolate, and thus the whole methylation cycle will be perpetually compromised.

    My contention is that people with the double mutation are required to take large doses of methyfoalte for life in order to have proper functioning methylation.

    Now yes I do believe you can give someone too much methyfolate leading credence to your theory of over-driving the methylation cycle, however again, those are probably the individuals with NO SNP's on C677T, and I am willing to bet those with ME/CFS who have NO mutations are probably in the extremely low minority. Don't let the minority create a rule of thumb....

    And now add to this your latest findings.
    http://forums.phoenixrising.me/inde...tion-cycle-block-hypothesis-for-me-cfs.15701/

    "3. The state of oxidative stress worsens as a result of the depletion of glutathione, and peroxynitrite rises, due to reaction of rising superoxide with existing nitric oxide.

    7. The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma [NOTE: THIS STEP WAS CONTRIBUTED BY PROFESSOR MARTIN PALL, BASED ON PUBLISHED LITERATURE, FOR WHICH I AM GRATEFUL.]

    8. The above process depletes the intracellular folates in general (as inferred from measurements with the methylation pathways panel)."

    Ok so now the RDA of metylfoalte really isn't going to cut it, if we can expect a good portion of ingested methylfolate to be catabolized via peroxynitrate. It would be interesting to see if there was a % rate of catabolization. Is it 20% or 90%? It's probably different for everyone. Can this be measured?

    In summary I really think the dosage of methylfolate needs to be examined and needs to be increased substantially. I also think genetic testing on the MTHFr gene is crucial in terms of trying to figure out proper dosage.
     
  2. TheMoonIsBlue

    TheMoonIsBlue Senior Member

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    Are there people WITHOUT the 2 most common MTHFR mutations that respond well to Methylfolate?

    Is there a need for Methylfolate even without the mutations?

    Are all the people, for example, who take Deplin for depression, positive for the MTHFR mutations?

    Just wondering if Methylfolate can work in positive way even for those without the mutations.

    (Although I understand to make sure you had NO mutations you would need further testing beyond just the two most common, is this correct?)
     
  3. Gestalt

    Gestalt Senior Member

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    I'm not sure where I saw it, but somewhere I saw that supposedly 98% of Autistic children have at least 1x MTHFR mutation.

    So that means 2% may not need methylfolate, however there are other issues in areas of the methylation cycle where support is needed.

    [​IMG]
    http://www.aacc.org/publications/cln/2011/january/Pages/FolateMetabolismFigure.aspx

    And yes it is very likely and I would assume that people who respond well to methylfolate have the mutation/s.

    Hypothetically even if you had no gene mutations on MTHFR, you could still have mutations on DHFR & SHMT or inadequate support for those enzymes that could impair 5-MTHF production. So thus in those cases supplementing methyfolate is still beneficial, if not necessary for optimal health.

    Also if someone had inadequate dietary folate/folic acid, B2 or B6, then methylfolate would help, but then you may as well just supplement those precursors instead.
     
  4. adreno

    adreno Homo neanderthalensis

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    I think you only risk overdriving the methylation cycle if you take the methylfolate with simultaneous high levels of methylcobalamin.
     
  5. TheMoonIsBlue

    TheMoonIsBlue Senior Member

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    So finding the right balance between Mfolate and Mb12 is crucial?

    What doses do you take of both?(assuming you are taking both) Do you take Adb12 also?

    Interesting that there has been for years a warning that excess folic acid "could cause cancer" but with Methylfolate there is not this warning, and very high doses are prescribed.

    I tested negative to the 2 common MTHFR mutations, but have not had any fuether testing.

    I am just wondering if people w/o the mutations may still need Methylfolate, just lower doses.
     
  6. Gestalt

    Gestalt Senior Member

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    I remain very skeptical of this notion of "overdriving the methylation cycle" and it appears to be a thought experiment assumption, rather than an observed phenomena. Where is the evidence for it?

    Overdriving implies there is a speed to the methylation cycle, and that the speed can be controlled by increasing/decreasing supplements dosage. However wouldn't there be some sort of regulating feedback mechanism? How does the body control methylation speed?

    I think for those who are very ill, and have a double mthfr mutaiton, it is still prudent to ramp up on methyfolate slowly, because of all the effects it has down the line. However for closing in on optimal health, those with the mutations it would appear they require more than RDA of methyfolate.
     
  7. TheMoonIsBlue

    TheMoonIsBlue Senior Member

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    Am I correct that a lot of autistic kids still have trouble with MB12 though, even if they respond well to Methylfolate?

    I am just trying to figure out the balance between the two. And if a person take high doses of Methylfolate, does that require an extra "need" for B12?

    I see a lot of people on Deplin for depression dont seem to be supplementing with B12 at all from a lot of the posts I have read online.
     
  8. Gestalt

    Gestalt Senior Member

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    Yes, B12 has it's own issues some of which are independent of the status of methylfolate.

    Dosage of metyhfolate in my opinion will depend on the efficacy of your personal folic acid cycle genetics and the existence of peroxyntirite. Dosage of B12 is typically considerably more complicated to determine and relies on a lot more factors than just methyfolate status. However 2-4g b12 should be safe.

    Since the MTHFr gene mutation is relatively common, for those who it works well for depression, it may be the only critical area that needs supplementing for them.
     
  9. Gestalt

    Gestalt Senior Member

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  10. drex13

    drex13 Senior Member

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    I'm hetero for both MTHFR SNP's (677 & 1298). I have not tried supplementing with any type of high dose of methylfolate, but maybe I'll give it a shot, as I do have depression and anxiety issues. I have a very difficult time with methyl b-12.
     
  11. Jenny

    Jenny Senior Member

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    Thanks for the chart Gestalt. Does anyone know what the evidence is for these percentages of reduced enzyme activity? I'm 677CT ++ and 1298 AC --, so it's alleged I have 60-70% reduced activity. If I thought this info was reliable I would up my methylfolate dose.

    Interesting there's no percentage reduction given for 677CT++ and 1298 AC++.

    Jenny
     
  12. richvank

    richvank Senior Member

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    ***Hi, Gestalt.​

    ***I welcome your comments on choosing dosages of methylfolate and B12 and on the question of the possibility of overdriving the methylation cycle. This is very timely from my point of view, since I'm currently considering possible changes to the simplified methylation protocol that I've suggested. My responses are at the asterisks below:​

    I have seen Rich mention this as a concern, however I would like to examine this a bit more closely. My primary issue here is with the seemingly incredible low dose of methylfolate on the Simplified Methylation Protocol. 400-800 micro grams of folate as according to RDA. But my question is since when does anyone take RDA of anything in order to get better!? When someone is sick do you recommend 60mg of VitC because that's what the RDA says?



    ***Your point about RDAs in general and vitamin C in particular is well taken here. The basis for the dosages of the folates that I suggested in the simplified methylation protocol was the experience of Dr. Amy Yasko. In 2007, when I was asked by Dr. David Bell to come up with a protocol based on the Glutathione Depletion--Methylation Cycle Block hypothesis that I had just proposed, with the help of a PWME who had been on the full Yasko treatment program, I extracted part of it to form a simplified protocol. Dr. Yasko had found that dosages of the folates near the RDA had worked well for both children with autism and adults with neurological diseases, so I adopted them.​

    ***As I've posted in the past, there is nothing sacred about the protocol I've suggested, and it has not been optimized. I have been continuing to adjust it as we have learned more from using it and from the experiences people are having with other protocols.​

    ***I do think that it's worth noting that about two-thirds of the patients in our clinical study did report significant improvement. That is not to say that there might not have been greater improvement with different dosages of the supplements, just that the dosages used did seem to help quite a few.​

    My understanding is that RDA is one of those antiquated protocols that was based on the absolute bare minimum required of a specific nutrient to not come down with something like scurvy. And on top of that when the protocol was created back in the 60's nutrients from food were considerably more abundant due to less over-farming and less pesticide/herbicide use.

    ***You are correct about the basis of the RDAs in terms of preventing the frank deficiency diseases. However, my understanding is that the RDAs do not depend on intake of nutrients from food. That is, they include what comes in from food.​



    Other ND's such as Jared M.Skowron are giving child patients 10mg a day of methylfolate and having incredible results within days of administering! (source)

    ***That's very interesting! Are these autistic patients? Does he give B12 also?​

    "A complete lack of dietary folate takes months before deficiency develops as normal individuals have about 500–20,000 µg of folate in body stores." (source - http://en.wikipedia.org/wiki/Folate)

    If normal people can store folate of up to 20mg then and their reserves are constantly being topped off via diet, then yes it is reasonable to understand why RDA of folate might be so low.


    ***Yes. I think the kidneys are very good at reabsorbing folate, so that not much is lost by excretion.​

    But now we must consider mutations on the MTHFr gene and prevalence. It doesn't matter how much folate your body stores or you get in your diet if you have a down regulation of 5-MTHF production.

    According to Dr.Ben Lynch in regards to mutations on MTHFR C677T
    1 SNP = 40% loss of function
    2 SNPs = 70% loss of function


    ***Yes, that's why it's important to give at least some of the folate as methylfolate.​

    What's more according to statistics about 40% of people globally have an SNP on C677T. With 15% of the people having two variants, resulting in 70% loss of function. Now what is the estimated global rate of CFS/ME? Might there be a correlation?

    ***The prevalence of ME/CFS is much lower than that. With tight case definitions, the studies usually come out with a few people or a few tenths of a person per thousand.​

    I would venture to guess yes. Most...80%+ of people with ME/CFS probably have at least 1 if not 2 SNP's on the very gene that codes for the enzyme that creates methylfolate. This is why I believe gene testing is so important. And also why in most cases PWME need to have much higher doses of methyfolate than the RDA...


    ***We looked at that a few years ago in the Yahoo cfs_yasko group, and it's true that most had at least one copy of at least one of the two SNPs (677 or 1298).​

    Looking a the the following results seems to prove my point.
    [​IMG]
    5-MTHF levels barely moved! You could stick people on the RDA of methylfolate for years, and because of the mutaitons on the C677T gene and lack of controvertible stores, people will be chronically low and undernourished with methyfolate, and thus the whole methylation cycle will be perpetually compromised.

    ***Perhaps, but note that SAMe and glutathione did come up to normal, on the average, by 9 months.​

    My contention is that people with the double mutation are required to take large doses of methyfoalte for life in order to have proper functioning methylation.

    ***Maybe. It would be good to look at people who have these SNPs but don't have ME/CFS, though. They may be running with higher homocysteine, and that's not too helpful in the long run, so they could probably benefit from some supplementation.​

    Now yes I do believe you can give someone too much methyfolate leading credence to your theory of over-driving the methylation cycle, however again, those are probably the individuals with NO SNP's on C677T, and I am willing to bet those with ME/CFS who have NO mutations are probably in the extremely low minority. Don't let the minority create a rule of thumb....


    ***I should probably reiterate here what the philosophy behind the simplified protocol was and is. It's a compromise. It's not intended to be optimum, since as you note here, the same protocol is not going to be optimum for everyone. It's intended to be a protocol that is accessible from a cost and complexity standpoint to the maximum number of PWMEs. Those who can afford it, and have the cognitive ability, can certainly get their genomics characterized and follow the full Yasko protocol or something similar if they choose. That was the path I originally advocated, but it soon became clear that that approach was not accessible to many PWMEs. The simplified protocol is a place to start. If it helps a person, the person gets more interested in this type of approach and is more willing to devote more of their limited financial resources to this type of treatment, and hopefully their physician will get more interested as well. As their health improves. hopefully their cognitive abilities will, too.​

    And now add to this your latest findings.

    "3. The state of oxidative stress worsens as a result of the depletion of glutathione, and peroxynitrite rises, due to reaction of rising superoxide with existing nitric oxide.

    7. The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma [NOTE: THIS STEP WAS CONTRIBUTED BY PROFESSOR MARTIN PALL, BASED ON PUBLISHED LITERATURE, FOR WHICH I AM GRATEFUL.]

    8. The above process depletes the intracellular folates in general (as inferred from measurements with the methylation pathways panel)."

    Ok so now the RDA of metylfoalte really isn't going to cut it, if we can expect a good portion of ingested methylfolate to be catabolized via peroxynitrate. It would be interesting to see if there was a % rate of catabolization. Is it 20% or 90%? It's probably different for everyone. Can this be measured?


    ***That's a question that Marty Pall and I have struggled with, and I don't have an answer for it. All I can suggest is that it must not be too high, or we would not have had as much success as we have with the dosages we used. Of course, once glutathione starts coming up, peroxynitrite is going to go down, and there will be less loss of methylfolate to this reaction.​

    In summary I really think the dosage of methylfolate needs to be examined and needs to be increased substantially. I also think genetic testing on the MTHFr gene is crucial in terms of trying to figure out proper dosage.


    ***If a person has the resources, I think that knowing the SNPs can indeed be helpful. On the other hand, there have been quite a few people who didn't go that route and have had pretty good results.​

    I'm not sure where I saw it, but somewhere I saw that supposedly 98% of Autistic children have at least 1x MTHFR mutation.​

    ***It's not quite that high, but there is a correlation between having an MTHFR SNP and having autism.​

    So that means 2% may not need methylfolate, however there are other issues in areas of the methylation cycle where support is needed.​

    I remain very skeptical of this notion of "overdriving the methylation cycle" and it appears to be a thought experiment assumption, rather than an observed phenomena. Where is the evidence for it?​

    ***I have seen lab test data (methylation pathways panel and plasma amino acids panel) from three people who had been on high-dose methylfolate together with high-dose methyl B12, and they showed what seems to me to be evidence of this. Namely, they had plenty of methionine and SAMe, low cystathionine and glutathione, low glycine and high sarcosine.​

    Overdriving implies there is a speed to the methylation cycle, and that the speed can be controlled by increasing/decreasing supplements dosage. However wouldn't there be some sort of regulating feedback mechanism? How does the body control methylation speed?​

    ***The rate-limiting enzyme in the methylation cycle is methionine synthase. It requires homocysteine and methylfolate as reactants and methyl B12 as a coenzyme. Normally the cells regulate the rate of the methionine synthase reaction by several feedback mechanisms. The amounts of methylfolate and methyl B12 are normally controlled. However, when large amounts of both are supplemented, the cells no longer have control over the rate of the methionine synthase reaction, and it speeds up, raising the rate of the methylation cycle. This has the effect of tending to raise the ratio of SAMe to SAH, which would raise the rates of the many methyltransferase reactions in general and would have major effects on gene expression and the biochemistry. However, the glycine N-methyl transferase reaction is there to limit the SAMe to SAH ratio. It does so by draining off methyl groups to convert glycine to sarcosine, which is why glycine goes down and sarcosine rises. Sarcosine delivers its methyl group to tetrahydrofolate, forming methylene tetrahydrofolate. This can then either go to form thymidine for new DNA formation, or it can be converted back to methylfolate by the MTHFR reaction. If the latter occurs, methylfolate delivers the methyl group back to the methionine synthase reaction, so this forms a sort of futile cycle. Meanwhile, the flow of homocysteine into the transsulfuration pathway is deficient, because homocysteine is being rapidly converted to methionine. Thus, the synthesis of cysteine is deficient, and therefore glutathione synthesis is, as well.​

    I think for those who are very ill, and have a double mthfr mutaiton, it is still prudent to ramp up on methyfolate slowly, because of all the effects it has down the line. However for closing in on optimal health, those with the mutations it would appear they require more than RDA of methyfolate.​

    ***I agree that the amount needed probably varies some from one person to another. I also agree with starting slowly. I've received quite a few reports from people who found the RDA levels of folates to be too high for them, especially at first. Some people have reported that they can tolerate only a crumb of the B12 and folate supplements.​

    Yes, B12 has it's own issues some of which are independent of the status of methylfolate.​

    Dosage of metyhfolate in my opinion will depend on the efficacy of your personal folic acid cycle genetics and the existence of peroxyntirite. Dosage of B12 is typically considerably more complicated to determine and relies on a lot more factors than just methyfolate status. However 2-4g b12 should be safe.​

    ***I think you must mean milligrams rather than grams here, right?​

    Since the MTHFr gene mutation is relatively common, for those who it works well for depression, it may be the only critical area that needs supplementing for them.​

    ***For many years, high doses of B12 have been injected in ME/CFS, and it has been helpful. but has not brought recovery. It was only when we began combining active forms of folate with high-dose B12 (injected or sublingual) that we began to see some recoveries. This was based on success with this approach in autism.​

    ***Likewise, I don't think methylfolate alone will work in ME/CFS, because of the functional B12 deficiency. I think it requires some of both to get methionine synthase going, and I think that's the key.​

    ***Thanks for your comments.​

    ***Best regards,​

    ***Rich​
     
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  13. Gestalt

    Gestalt Senior Member

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    Thanks, for your thoughtful analysis.
    Yes, this is partly why I posted this. Hope it helps formulate a better plan.

    Yes, I believe you are right. I stand corrected.​
    I am not sure if you click on this link, he talks about the two cases.

    Interesting, you wouldn't happen to know what form the body stores & reabsorbs folate would you? Is it THF?​

    I find it interesting that there isn't a direct linear like correlation between 5-MTHF levels and SAMe and glutathione. Seems B12 is more important for those aspects. However based on your above charted results, it would seem a good dose of 5-MTHF might be...

    Since 800mcg, collectively on average raised the level from what looks like 10 to 20 or 10 basis points, then to go another 20 basis points would mean 800mcg x 3 = 2.4mg per day.

    I know metyhfolate is used for other process other than just B12, such as in DHFR in the pathway from 7,8-Dihydrobiopterin to BH4. Might there be other purposes of methylfolate in the body?
    Couldn't all this be explained better via the up-regulation MTR A2756G defect? I mean wouldn't that make more sense given the results?

    My understanding is that a normal enzyme only works at a given speed, and doesn't work faster if there is more stuff for it to chew on. Now a faulty up-regulated enzyme would work faster...
    Yes I did mean mg. Thanks for the correction.
     
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  14. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Just as a note, I do not have either SNP (677 or 1298). yet I tested out of range on 12 of the 13 values on the methylation panel before treatment. So I guess I am one of the minority.

    Best,
    Sushi
     
  15. Gestalt

    Gestalt Senior Member

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    Yes and No. Minority on mthfr yes, but probably not on all the other genes that regulate the methylation cycle. According to heartfixer CBS upreg occurs in 90% of people tested. That's pretty crazy. If that's really the case supplementing for CBS mutation as part of the generic protocol may even be more beneficial than trying to help mthfr.

    I wonder if yasko has a database of CFS/Fibro to see if she can check prevalence of genes, and then based on the highest % defects, formulate a supplement protocol off that. Might be of great benefit to you Rich.
     
  16. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Hi Gestalt,

    If you are online, open a chat with me and I can direct you to some data.

    Sushi
     
  17. caledonia

    caledonia

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  18. Gestalt

    Gestalt Senior Member

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    That's awesome. Thanks for that caledonia. I think that's a great place to start for further fine tuning of a CFS protocol.
     
  19. adreno

    adreno Homo neanderthalensis

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    This fits well with research I have posted earlier:
    http://forums.phoenixrising.me/inde...n-and-healing-occurs-at-1000mcg-folate.15016/
     
  20. greenshots

    greenshots Senior Member

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    sadly, 1+1 doesn't = 2 in methylation. You have some logical observations but its not that simple when you look at all the defects and how they interact. The AHCY defect can benefit the MTHFR C677T but it can offset the benefits it would have had on a normal COMT activity. The COMT defect often allows kids to remain verbal since it spares dopamine so it can be a good thing. But the VDR Taq effects the COMT defect's status. Then there's the MTRR and how it effects the SUOX enzyme. It goes on and on and on. There is a domino effect that supercedes any ability to evaluate a single variable, its more like 1,0000 variables. We all understand the fact that we are overloaded with folic acid in the food supply, so we need to focus on the other competition. In my experiences with family, friends, my biomed gp, and myself, when you hit one area too hard thinking to balance it, you almost always throw something else out of whack. Its inevitable. Only then you've moved so far past your new changes that you don't know whats even doing it anymore and either forge thru or stop everything and lose time.

    Your'e right though, outta thousands and thousands of autistics, only a handful didn't have even one of the MTHFR defects. They'd have nasty defects in other areas like a double CBS + ACAT and MTRR or something close. BTW, Yasko has seen a pattern where the MTHFR 3 is even worse for adults then the C677T. I'll just bet more findings will rear their ugly heads in the future.

    Also, Yasko isn't focused on CFS so even though she does keep track of the data somehow, she won't be going away from the kids to formuate a plan just for CFS. She does have some basics though and I know my doc looked at them and only liked half of them, I think. But then, she's alwaysbeen against an autism or cfs bundle anyway. She thinks each person has to be taken differently and treated that way, too.
     

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