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Rich - possible causes of methylation cycle block?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by caledonia, Mar 25, 2011.

  1. caledonia

    caledonia

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    I have been puzzling over this lately. What are the possible causes of a partial methylation cycle block? Genetics is supposed to be one, but what if you don't necessarily have the genetics for it?

    For example, I have only one MTHFR SNP out of a possible four. My naturopath thought that was iffy as to whether I had a block. Then when I got the Vitamin Diagnostics Panel, I definitely had a block and a classic CFS pattern.

    And back when people were doing the DNA test their results were all over the place and didn't seem like genetics predicted anything except the CBS/sulfur?? thing. It's been awhile, can't totally remember.

    I know you mentioned Judy M and Jill James are looking at whether XMRV causes this.

    And I also found an interesting interview with Martin Pall which seems applicable:
    http://www.chronicfatiguetreatments.com/wordpress/treatments/interview-with-dr-martin-pall/

    I think he's saying that a short term stressor would cause a short term problem with the methylation cycle. It doesn't make any sense to me that a short term stressor would cause a chronic problem, otherwise everyone would get a cold, for example, then be sick forever.

    Therefore, it also sounds like you would need a chronic stressor to create a chronic problem.

    In the absence of an obvious chronic stressor, then you're left with things like food sensitivities, toxic mold exposure, Lyme, or XMRV.

    Comments?
  2. jeffrez

    jeffrez Senior Member

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    mercury, for another major one. It screws up important methylation related enzymes and also inhibits transport of B12 across the blood brain barrier.
  3. FunkOdyssey

    FunkOdyssey Senior Member

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  4. Freddd

    Freddd Senior Member

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    Hi Caledonia,

    Just two weeks ago I found what was causing methylation block for me over and over again to the extent of causing poor cell formation, folic acid and folinic acid. I don't know what percentage of people that is true for but it appears to be the case at least for all those who respond to folic/folinic acid with "detox" symptoms also called paradoxical folate deficiency.
  5. richvank

    richvank Senior Member

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    Hi, Caledonia.

    You've raised a lot of good questions. I've addressed most of the issues you've raised in my papers starting in 2004, which can be found on Cort's site at http://aboutmecfs.org.violet.arvixe.com/Trt/TrtGSHIntro.aspx

    However, I will try to hit the high points here.

    Genetics: I believe that there is a genetic predisposition to ME/CFS, for several reasons: There have been twin studies and family tree studies that point to this being the case. There are SNPs that have been found at higher frequency in PWCs than in the general population. There has to be a reason why everyone doesn't get ME/CFS. It appears that it is not just one SNP that is involved in this genetic predisposition, but a set of SNPs that affect the same biochemical pathways. As you noted, the set is not the same for everyone, but the collection of them impacts the same certain pathways in all the PWCs. It's the overall impact on the pathways that matters. Which pathways? This isn't completely nailed down yet, but I think the methylation cycle, folate metabolism, and glutathione system are most likely involved. Perhaps the detox system, the wider antioxidant system, the immune system (including the HLA genotypes), and the stress response systems would be good candidates for inclusion, too. I wish we had more data on polymorphisms in the enzymes and other proteins in all these systems. If we did, I think we could answer this question.

    In addition to the genetic predisposition I have suggested that some combination of a variety of stressors, which can be physical, chemical, biological and/or psychological/emotional is necessary to bring about onset of this disorder, and long-term stressors seem to be particularly devastating in this regard, as you suggest. I believe this for several reasons. First, I have received histories from many PWCs, and the events that preceded the onset of their illnesses featured this whole range of stressors, and in many cases, they were piled on top of each other, as in a "perfect storm." Second, I have studied the published "risk factor" studies for ME/CFS and they show the same thing. Third, it is a fact that the body deals with this whole variety of stressors by means of the nonspecific stress response systems (in addition to making specific responses to the various stressors). The nonspecific stress response systems come down to secreting cortisol, epinephrine, and norepinephrine.

    When these substances are at high levels for long times, the result is a major demand on glutathione. This seems to be a unifying feature. Furthermore we have measured glutathione in many PWCs now, and it is usually depleted. If not, it seems that there are SNPs in the enzymes that use glutathione, giving much the same result. Glutathione is at the basis of the antioxidant enzyme system, so when it goes down, oxidative stress ensues. Oxidative stress is probably the best documented biochemical abnormality in ME/CFS.

    It is known that one of the roles of glutathione is to protect vitamin B12 from reactions with toxins. When glutathione is depleted, B12 is unprotected, and a functional deficiency in B12 results. This is evidenced by a rise in methylmalonate, and we have seen this in a large number of PWCs by now.

    When B12 becomes functionally deficient, it is unable to perform its two roles in the body. One of these failures gives rise to methylmalonate. The other robs methionine synthase of its necessary coenzyme, methylcobalamin. When that happens, this enzyme becomes inhibited, and both the methylation cycle and the folate cycle experience a partial block. This shows up directly on the methylation panel, and it also shows up as a rise in figlu on the urine organic acids panel.

    What about XMRV? There's a lot we don't know about this yet. However, we do know that methylation silences the expression of retroviral genes, and we also know that glutathione favors viral activity in general. A partial block in the methylation cycle and glutathione depletion would favor the retroviruses. It is possible that they have developed ways of bringing this about. It could also be that they rely on their "cousins," the herpes family viruses or other viruses that survive in the body in the latent state, to do this for them.

    With regard to Marty Pall's model, my opinion is that it is subsumed within the model I have proposed. In other words, I believe that the reactions he discusses do occur, but they result from the partial block in the methylation cycle, rather than being the cause of it. The stressors he mentioned all place demands on glutathione. I think it's likely true that nitric oxide rises, but I think that's result of the lowered production of assymetric dimethyl arginine, which is normally the main inhibitor of nitric oxide synthase. A partial methylation cycle block causes less production of this inhibitor, and that allows nitric oxide to rise. Peroxynitrite also rises, but I think this is mainly a result of the rise in superoxide, which reacts with nitric oxide to form peroxynitrite. Superoxide rises because of glutathione depletion, which produces a rise in hydrogen peroxide, and that causes superoxide to rise.

    It's true that some of the stressors are short term stressors. However, if the load of stressors is severe enough, a vicious circle can become established. This is an unnatural positive feedback system that perpetuates itself. I have suggested that the combination of glutathione depletion and a partial methylation cycle block is the vicious circle that causes ME/CFS to be chronic. I think this is supported by the observation that when methionine synthase is supported with high-dose B12 together with active folate, both the methylation cycle partial block and glutathione depletion are observed to be corrected.

    When this system is operating normally, short term stressors that cause oxidative stress do temporarily shut down methionine synthase, and this causes more of the homocysteine to be diverted into the transsulfuration pathway, to make more cysteine, which can be used to make more glutathione, to counter the oxidative stress. Once this problem has been overcome, methionine is allowed to resume converting homocysteine to methionine. In ME/CFS, this normal regulatory function is driven out of operation, and the system gets "stuck" in a vicious cycle. But it can be restored to normal by boosting methionine synthase with simultaneous active, reduce folate, and high dose B12.

    Best regards,

    Rich
  6. Freddd

    Freddd Senior Member

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    Hi Rich,

    I have a question concerning folate. In the circumstance when folic acid or folinic acid causes the near immediate failure of cell reproduction such as the impaired reproduction leading quickly to angular cheilitis and acne type lesions and far more if allowed to continue, does this then idicate failure of the methylation cycle. It appears to shut down the cell reproduction within 6 hours. As is frequently mentioned in to b12/folate research, there is a triage effect as some things requiring these transactions shuts down before other transactions do. That can be observed if this shutdown is allowed to progress for weeks, months and years. So would the imperfect cell reproduction quickly caused by induced folate deficiency be a leading indicator of methylation failure and if it isn't what else is it?
  7. richvank

    richvank Senior Member

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    Hi, Freddd.

    I've read your recent posts reporting that both folic acid and folinic acid have produced symptoms indicating that cell reproduction has been impaired in your case. I have found this to be puzzling. Add this to your unhappy reaction to glutathione.

    These are unusual responses, freddd. People generally respond well to both folic acid and to folinic acid, and glutathione is usually either helpful or innocuous.

    I've been trying to figure out if there is a common factor that would explain these unusual reactions to all three of these supplements.

    I think I've found a possibility, but I don't know if it's the answer, so I'm just going to put it out there as something to look at and kick around.
    The possibility I've come up with is that you have a deficit in NADPH. If such a deficit were present, taking folic acid would place a demand on it, because two molecules of NADPH are needed to reduce folic acid to tetrahydrofolate, and this would compete with the pathway that makes thymidylate, which is needed to make DNA for cell reproduction, since this pathway produces dihydrofolate also, and a NADPH molecule is needed to reduce that to tetrahydrofolate.

    Similarly, taking folinic acid would place a demand on NADPH also, because it would require NADPH for the 5,10-methylenetetrahydrofolate dehydrogenase reaction, which is in the pathway for producing L5-methyltetrahydrofolate from folinic acid. So this could also suppress the thymidylate synthase reaction and DNA synthesis. I think you reported that folinic was not as bad as folic for you, and that would correspond with its demand for only one NADPH molecule, rather than two, as folic acid requires.

    And glutathione, after it becomes oxidized, must be reduced by glutathione reductase, which also requires NADPH.

    Here's another interesting fact: In order for a cell to remove the cyanide from cyanocobalamin, it needs to use NADPH.

    Well, if this is indeed what is going on, what would cause a deficit in NADPH?

    The most common cause would be an inherited genetic deficiency in glucose 6-phosphate dehydrogenase (G6PD). There is a wide variety of polymorphisms that can cause this. If you had a severe form of it, though, I think it would have been discovered a long time ago, because it would produce hemolysis of the red blood cells. But maybe you have a mild form of it.

    Polymorphisms in other enzymes in the pentose phosphate shunt could cause low NADPH also.

    Anyway, low NADPH is the only common factor that I have been able to find that could cause deleterious reactions to all three of these normally helpful substances. Let me know what you think about this.

    Best regards,

    Rich
  8. Freddd

    Freddd Senior Member

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    Hi Rich,

    I'm going to have to do a little reading on this, and not tonight. However, it could be a unifying factor on all this. This takes the three things and looks for the least multiplying of root causes. So now I have a few questions. First a clarification on the difference between folic acid and folinic acid. A single dose of folinic acid 800mcg in a mixed group of supplements including 400mcg of folic acid in B-Right with a meal succeeded in a month of slowly causing deficiency. At that time I was taking 3 Metafolin with each meal and a couple more with each b12 injection (3x daily). I did substitute the folinic acid for one of the Metafolin. When I took the folic acid 400mcg twice a day without Metafolin at the same time I also slowly developed a folic acid deficiency, sometimes. The variability was confusing. It all gelled when I upped my usage of the adb12 with folic acid to go along with the methylb12 sublinguals and injections. I started seeing symptoms in a few days and they were full blown in a week despite 2400mcg of Metafolin at the same time. Then, after you had mentioned competition for the absorption and transport I tried a Metafolin 15 minutes before the meal, the B-right with Metafolin (competing strongly for the absorbtion and transport systems) at the end of the meal and reduced to 2 Metafolin with each injection and the symptoms started improving within hours, and yes, I can feel the direction the cheilitis is going and it's change. So while it is there it is an ultra sensitive indicator. I had hypothecized that because the effect of the folinic acid and it's known longer serum halflife compared to folic acid, and Metafolin, that it had a prolonged effect causing more damage than 3 separate folic acid doses a day as long as there was Metafolin taken at the same time as the folic acid and that it outlasted the Metafolin thereby causing the problem. As I mentioned at the time I was displeased that my balance was so delicate that I could be triggered into folate deficiency that easily. So, as long as I took folic acid no more than 3 times per day and each time with Metafolin and additional Metafolin at other times I didn't normally have folate deficiency symptoms. If I took it in 5 doses thoughtout the day with Metafolin I had symptoms. However, if folinic acid was taken with one of those doses each day I developed symptoms slowly. So actually I considered the folinic acid to be WORSE than the folic acid and attributed it to serum halflife. So playing the "competiton" hypothsis I was able to counteract the folic acid except when it was in 5 divided doses per day and/or possibly because of sublingual absorption bypassing part of the competiton in the absorption system.

    However, this is by no means rare. 100% of those taking active b12s and active folate had the same reaction to glutathione as I had but not all as severe. Some significant but still unknown percentage here and at wrongdignosis respond to folic and/or folinic acid in the same way I do but probably not everybody. When I first started posting here I commented on all the people who where having "detox" reactions from hycbl/folinic acid that wasn't being seen with mb12/adb12/folic acid I said that this was the same artifact that I saw with people taking cyanocbl/folic acid or hycbl/folic acid. I called this an artifact of these substances and was startled by the high incidence of this. Having had all the same "detox" reactions now involving glutathione, folic acid and folinic acid as other people also having those same "detox" reactions to glutathione, NAC, folic acid and folinic acid, and that invloved 100% of those trialing glutathione who were also taking active b12s plus Metafolin, I have my doubts, in all directions. These things all occur, and over the last 2 weeks more people are having experiences switching to Metafolin from folinic/folic acid and the changes appear to be right in line with mine, and more are switching each day. It isn't rare. There are plenty of people at both sites with these responses.

    I would like to see some folks deliberately try to induce the folic/folinic acid reaction, stopping and reversing it as soon as they can confirm it. Without Metafolin at the same time each dose of folic acid appears to have an action time of about 8 hours where as even with Metafolin the folinic acid had an action time of 24 hours.

    I am reasonably certain that the glutathione "detox" reaction can be induced in anybody who has previously gotten rid of the folate deficiency symptoms so they can see it when it hits them. If they have never removed the folate and active b12 deficiency symptoms nothing changes with glutathione so it appears to have no detrimental effect. Some of the people who hadn't been on the active b12/folate do develop glutathione "detox" because they previously didn't have the folate deficiency symptoms and therefore had something to compare to. Again, I am sure some people have this reaction to folic/folinic and never know it. That was happening to me. I had absolutely no way to know it was happening until after I tried the Metafolin and succeeded in having lifelong folate deficiency symptoms go away. I did know that folic acid wasn't terribly effective for me. I couldn't know that it blocked active folate, and probably from food too, until I was able to experience it after starting metafolin and having such a pronouced response to it. I would suspect that just about every body who has a strong response to Metafolin after folic/folinic acid is having the same blocking response from folic/folinic acid.

    I am very interested in the NADPH possiblity of playing a part, or one of several parts. I have always suspected that I had multiple interacting things going on because of the head spinning changes of direction and hypersensitive reponses to to everything surrounding b12 and folate. It's not that I respond differently than most, I respond faster, harder and more distinctly than most others, but not differently.

    People generally respond well to both folic acid and to folinic acid, and glutathione is usually either helpful or innocuous.

    I think that the ONLY reason this is so is that they already have deficiency symptoms so they see no changes. They don't have a basis for comparison. I would bet that out of a selected population of active b12/active folate responders that essentailly 100% will have the same reaction to glutathione as I do, given sufficient dose. And if folic/folinic acid doesn't work for them how would they EVER know until they take Metafolin without any one of those 3 blocking agents in their body? I think that this might be the factor in why a sizxable percentage ogf people are not having more strongly favorable reponses. Then when they do change to all active substances they have an ass-kicking effectiveness with Godzilla size startup overcoming the induced defciencies.

    I think that we will see a lot more information in the next couple of weeks. Lot's of people are trying the change, so we shall see.
  9. JPV

    JPV Senior Member

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    According to Cheney, CFS sufferers are low in NADPH, so I'm not sure that it's all that rare...


    More on Vitamin D3 and CFS
    December 24th, 2009 in Hormones in CFS
  10. Joopiter76

    Joopiter76 Senior Member

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    Hi to all,

    I posted somewhere about the NADPH defency in this forum. Usually PWCS are low in NAD and so they are low in NADH and NADPH as well. But this may not be the key. I suspected a general phosphorylation problem in CFS either because ion channels are controlled by phosphorylation and methylation. they high oxidated glutathion my not only be a result of the high oxidative stress but also a result of low regeneration. for regeneration of GSSG FADH and NADPH are needed. As I saw only low results with taking high doses of B2 I saw really good effect on GSH levels and GSSG levels by taking FMN which is a phosphorylated form of B2 (said easily) and the levels of GSH went up from 590 to more than 900. So I guess this is signifikant. I also tested low for pyruvate and low for citric acid which may indicate low G6PDH activity. People with G6PDH defency feel better eating more carbohydrates, because this will push NADPH and pyruvate synthesis.
    The other Question is how to improve NADPH? Is there any NADPH rich food I think it is usually in green vegetables. And another question is, what can block G6PDH ?

    Freddd maybe indole-3-carbinole could help you because it supports the p450 system and this system is usually uncoupled in CFS. I take it and it helped me.
    Maybe Mg-citrate is not so good because high citric acid may lower the pyruvate synthesis. I do not know which effect Mg-molonate woul dhave on this system, I guess it could even if not so much. I am thinking of using Mg-oxid to avoid this. What do you think Rich.

    By the way does someone (Freddd, Rich) know what is used as the cofactor when folic acid is converted to dihydrofolate? NADPH as well? NADPH is also needed for other steps in the methylation cycle.

    I wonder if there is a problem in phosphorylation of NAD?
  11. richvank

    richvank Senior Member

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    Thanks for posting this information, Freddd, JPV and Joopiter. Maybe all of this is coming together.

    JPV--Now that you mention this, I do recall Dr. Cheney commenting on it. I think he has measured NADPH in some of his patients, using the Health Diagnostics lab, I think.

    Freddd--When I said that the deleterious responses to folic acid, folinic acid, and glutathione are unusual, I was referring to the general population. If this occurs in many PWMEs/PWCs, it seems that that would be consistent with low NADPH in this cohort.

    Joopiter--NADPH is used to convert folic acid to DHF, using DHFR. I recall your comments about phosphorylation in CFS, but at that time I didn't know how that would fit in. I don't know whether a different form of magnesium would be better.

    Best regards,

    Rich
  12. lucy

    lucy Senior Member

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    Chronic problem, related to the movement - for me it sounds like vascular (vessels) or metabolic (muscle). Vascular problem fits in the picture of NO related problem, because the epithelium of vessels uses NO. If the uptake is compromised, there is constant overdose of NO. NO also regulates mitochondrial respiration. Still this theory does not explain fatigue after mental exertion.
    Maybe there would be a correlation between vessel issues in close relatives, like in my family we have varicose veins, which I have not (yet?) developed. I have raynnaud's (instead?). Even before getting ill, after a getting white fingers and toes I had to go to sleep to recover from profound fatigue when getting warm again.
  13. lizw118

    lizw118 Senior Member

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    I have similar vascular issues, including raynaud's and sinus headaches that only go away with vasoconstrictors. Is that an NO problem? What can be done about it?
    liz
  14. Joopiter76

    Joopiter76 Senior Member

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    What I meant about phosphorylation is, if there is ion channel dysfunction as it is reported and there is low result in taking B2 and much more result in taking FMN which is the next and phosphorylated product then this could be a hint to the problem adding a phosphate group. Same in p5p often low in CFS maybe due to kryptopyrrolurie but maybe due to low phosphorylation. And then low pyruvate could be also due to low activation of thiamine which also has to become phosphorylatet. And then low NADPH. So what?! I mean this could be one point under thousand, but I think there must be a general defect that leads to the cronic NO synthesis and chonic dysfunction of the whole body. Low NADPH could be a key factor that leads to depletion of GSH as well as low methylation cycle function and many other redox reactions. So it would be very interesting to see what would hapen if someone gets pure NADPH but as far as I know this is not available yet.

    I want to ad that many things like Vitamin C infusion, Copper, GSH, sulfites and so on can lead to a worsening of the symtoms and these all have an inhibitory effect on G6PDH. (YASKO)

    I also react badly to folic acid. And if the dose of folinic is to high as well, but a dose of folic acid up to 800mcg has helped me very much with my weakness.
  15. Cloud

    Cloud Guest

    Most of this is over my head (I was at the beach when we studied the Kreb cycle). But I am curious because it sounds as though supplementing GSH directly (IV or nasal spray) might be a bad idea if one is NADPH deficient. This would be especially true for cardiac cells because of their high energy demand. I guess depending on the cause for the NADPH deficiency, it seems that supplementing NADH and d-ribose would help with this problem (only drained my wallet)? So what is causing the NADPH deficiency? Is the test available?
  16. anne_likes_red

    anne_likes_red Senior Member

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    If Cloud was on the beach I had my head under the water. :)

    ..Anyway, re the occasional negative reactions they've seen with GSH supplementation, Jon Pangborn from the Autism Research Institute suggests supplements of magnesium malate as a possible nutritional strategy for producing more NADPH.
  17. Joopiter76

    Joopiter76 Senior Member

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    Are you sure he didn`t mean NADH because this is generated in the krebs cycle. NADPH is generated aoutside the krebs cycle.
  18. anne_likes_red

    anne_likes_red Senior Member

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    No thats what he said - though he also says NADPH is generated via citric acid cycle (malate to oxaloacetate) and via several other processes:


  19. Freddd

    Freddd Senior Member

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    Hi Rich,

    Another piece of information. Magnesium has been on the needed basics list for years and for some people is a critical showstopper. The reason I could come up with was reports that magnesium acted as a "substrate" in many b12 transactions. Something I have seen over and over, lots of hypothesis are superseded all the time in these things or refined with more specificity.

    Freddd--When I said that the deleterious responses to folic acid, folinic acid, and glutathione are unusual, I was referring to the general population. If this occurs in many PWMEs/PWCs, it seems that that would be consistent with low NADPH in this cohort.


    Could this be the selective factor we have all been looking for? People will have b12 deficiency symptoms regardless of serum level if methylfolate is hindered. At the b12 deficiency forum most people never know why they have b12 deficiency symptoms. It's pretty clear that diseases based on low b12/folate and who knows what else have been exploding which suggest something introduced into our lives in the last 50 years, which describes both cyanocbl/hydroxycbl and folic/folinic acid.
  20. Freddd

    Freddd Senior Member

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    Hi Liz,

    B12 has activity that regulates NO levels. Carmen Wheatly has written several specualtive papers on the role of b12 involving NO and inflammation. She was working with hydroxycbl being in the UK. I find that mb12 reduces inflammation very rapidly as does Metafolin.

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