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Question on TMG/betaine and methylation

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Lisa, Jul 21, 2010.

  1. Lisa

    Lisa Senior Member

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    Hello!

    I was wondering if the betaine HCl in my digestive enzymes functions the same as if I took that same quantity of TMG as far as the way it interacts with the methylation cycle. I'm guessing it does, but thought I'd ask in case someone knew for sure. :Retro smile:

    I'm using NOW Foods Super Enzyme and each cap has 200 mg Betaine HCl
    http://www.iherb.com/Now-Foods-Super-Enzymes-180-Capsules/857?at=0

    Thanks! Lisa :Retro smile:
  2. richvank

    richvank Senior Member

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    Hi, LIsa.

    As far as I know, it does. It's the same molecule, just has hydrochloric acid bound to it. This has been an ongoing issue, which I haven't been able to resolve in a straightforward way. As you probably know, the betaine homocysteine methyltransferase (BHMT) pathway is an alternative pathway that converts homocysteine to methionine in the liver and kidneys. In treating to lift the methylation cycle block in the other (methionine synthase) pathway, there is an advantage to have some flow going through the BHMT pathway, because it will provide SAMe, which is needed by methionine synthase reductase to recycle cobalamin when it becomes oxidized. On the other hand, Dr. Amy Yasko has argued that if the BHMT pathway is stimulated too much, the flow of homocysteine will be shunted into it too much, and not enough will be available to feed the methionine synthase pathway. That having been said, a couple of weeks ago I received an email "out of the blue" from an autism mom who wrote that adding TMG to her child's supplements was just what was needed, and she went into great detail about what her child could say and do now, that he couldn't before starting the TMG. She said she just had to tell somebody whom she thought would care! I definitely do care, and appreciated reading this. As you may know, I believe that a lot of the biochemical issues are the same in CFS and in autism. I just don't know whether the line should be drawn on TMG dosage for people with CFS.

    Many PWCs find that they need betaine HCl to build up their low stomach acid, in order to get their digestive system operating better, and some seem to need a lot of it.

    There is a diluted HCl solution sold by Allergy Research Group that can supply stomach acid without burning on the way down. Also, some people use lemon juice or even apple cider vinegar. If lemon juice is used, it's important to use a drinking straw and to flush the teeth with water afterward. Citrate is a chelator for calcium, and can damage the enamel on the teeth.

    I hope this helps.

    Best regards,

    Rich
    Lotus97 likes this.
  3. Lisa

    Lisa Senior Member

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    Hi Rich! :Retro smile:

    Thank you very much for replying to my question!

    Sounds a little like everything else with us, always variable. ;)

    I've been experimenting lately with apple cider vinegar for body ph but often forget about it as a digestive aid. Thank you for listing it.

    I have a follow up question but am not sure my facts are right so if its completely odd blame Google. :D

    I have a lot of chemical sensitivities as one of my main problems. From what I understand of Dr. Pall's work, the NO/OHNOO- cycle can block the methionine synthase pathway which can help lead to increased elevations of homocysteine.

    In which case, does it seem accurate that adding TMG/Betaine to a supplement regime could potentially provide some balance to homocysteine levels which otherwise might not be there? I could be totally off on my interpretation of the pathways. :Retro smile:

    I have found that too much Betaine (such as adding another enzyme to a meal)) will make me feel over stimulated for a dose or two but then passes. After a couple weeks I can add another with the same results, again feeling normal (or what passes for normal :tear:) within a few doses.

    How might one know if they have added too much?

    Have a beautiful day! Lisa:Retro smile:
  4. taniaaust1

    taniaaust1 Senior Member

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    Hi Lisa. My CFS specialist has me on TMG due to a polymorphism i have.. Betaine is a methyl donor.

    After I got put on this I went to the chemist and thou they dont stock the pure Betaine I use, they printed me off a write up on Betaine all based on research (several pages long) and gave it to me. From that it appears that TMG (which is 100% Betaine), is quite different to use then Betaine HCL. It refers to the differences in the info i have.

    eg "Betaine (especially the Trimethyglycine (TMG) form of Betaine) hlps prevent Cardiovascular Diseases"
    "Betaine (especially the Trimethyglycine (TMG) fom of Betaine) increases S-Adenosylethionine (SAM) levels"
    "Betaine (Betaine Hydrocholoride form only) facilitates the absorption of Folic Acid"
    "Betaine (especially the Trimethyglycine (TMG) fom of Betaine) lowers elevated Homocysteine levels"

    anyway.. you should get the gist from that (it says much more) that the 2 different forms are recommended to be used for different things

    also it says
    "Forms of Betaine
    *Betaine Hydrochloride consists of 76% Betaine combined with 24% Hydrochloride (HCL). It is used as a supplemental form of Hydrochloric Acid. SOME RESEARCHERS HAVE STATED THAT BETAINE HYDROCHLORIDE DOES NOT PROVIDE THE THERAPEUTIC EFFECTS ATTRIBUTABLE TO PURE BETAINE (TMG).
    * Trimethylglycine (TMG) is 100% Betaine and is purported to be the optimum form of Betaine for all uses other than correcting Hydrocholoric Acid deficiency.


    (the capitables in the above.. ive done and are not in orginal text).
    ........................

    Have you had your homocysteine levels checked? mine were at higher levels than its good that they be at.

    Pure Betaine (TMG) at 600mg per day didnt improve my CFS symptoms at all and didnt seem to do a thing for me (I didnt get my homocysteine retested...I only suppose it would of lowered that to a normal persons level).
  5. nitekitty

    nitekitty

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    I have to take TMG!

    Hi, I have the first documented case of a Betaine deficiency (TMG). My homocysteine was high so I went to Dr Mudd here at NIH in bethesda, md. How high was your homocysteine and what polymorphism do you have? What caused your high homocysteine?

    My homocysteine was 45 and taking 1000mg of TMG did not help at all to reduce the homocysteine. It wasn't until I was taking higher doses. Anyway, get back to me! Would love to hear from you.`

    Thanks,
    NK


  6. taniaaust1

    taniaaust1 Senior Member

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    I have a MTHFR polymorphism (affects folate.. one with this can only get half the amount of folate a normal person does... also it causes higher homocysteine levels). It affects the activity of enzyme 5,10 methylene tetrahydrofolate reductase, which converts homocysteine into methionine.

    A smart specialist first realised I probably had this issue due to my homocysteine being at 8.9 umol/L .. which is what appears to be well within normal range but at this level does actually indicate an issue, this is higher than a persons without an issue. 5-17% of people have this polymorphism (the rates depend on what part of the world you are in) and often fall within the normal lab range on the higher ends of it. Anyone with this level. thou probably has MTHFR polymorphism and then should have more tests done to confirm this or not. (I then got sent for a Thrombophilia genotypes test to confirm it).

    This polymorphism caused my daughter to be born with serious birth defects (which would of been preventable if i'd known i had this disorder before i got pregnant and was having supplementation for it), an issue similar to spina bifida!!! (caudal regression syndrome). Not only can it cause neural tube defects in unborn babes but it also can cause miscarriages, strokes, vascular disease and thrombosis etc etc

    Each increase of homocysteine of 5 umol/L increases the coronary and stroke risk by between 50-80% (hence why it still should be treated even if your homocysteine is within the higher ranges of normal).

    Appears in 10% of Caucasians.. one study in france showed a rate of 16.9% .. so this polymorphism is quite common and most unfortunately who have it, dont know they have it as doctors will usually ignore the homocysteine results as they still fall within normal ranges and are on the higher ends of normal (higher than the real what is truely normal and not an issue) and most doctors arent aware of this condition and what those results indicate.
  7. Lisa

    Lisa Senior Member

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    Hi taniaaust1! :Retro smile:
    I have not had them checked yet though I do have a doc who would surely be willing if I requested it. So many things to work on, I'm moving slow but starting to find my way through what works for me and what doesn't.

    Other than some hyperness or just being more awake, I haven't noticed much either. I had been looking over my list of supps I take and begun wondering what my enzymes were doing to the picture which then sparked the question here. :D

    Interesting stuff you posted, will have to give this some thought! Thank you for taking the time to copy some of that here! :Retro smile:

    Have a great day! Lisa :Retro smile:
  8. serg1942

    serg1942 Senior Member

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    TMG vs Betaine HCL


    Hi everybody,

    This is a question I really would like to solve…

    I cannot tolerate the supplements for the so called “long methylation cycle route”, via MS enzyme. I think it is because of the detoxification produced by restoring this cycle, as it is the precursor of glutathione and other substances needed to detoxify most of toxins.

    I cannot tolerate any supplement that directly detoxify heavy metals either, as ALA, NAC, DMSA, etc. This would explain my bad reaction to the “methylation supps”.

    However, I do need betaine HCL. I cannot afford the HCL Rich talks about, so if I want to digest, I have to take 3 caps of betaine HCL per meal. I take over 12-15 caps daily, and surely I’d need more than 30… (I am developing tolerance...)

    I do not feel any detox-effect from betaine-HCL, and although my last aminoacids test indicates a high activity of the enzyme BHMT (seen by sarcosine levels elevated, but in range), this should be normal as I am not supporting the other route (MS enzyme).

    So, according to my experience, and I don’t know why, it seems that betaine HCL doesn’t affect the enzyme BHMT, at least as much as pure TMG does…

    Now I am digressing. If in fact betaine HCL would affect BHMT as pure betaine (TMG) does, then the only explanation I can think of is: When I support the methylation cycle via the enzyme MS, I feel so bad, not because of detox, but because of immune system activation (This doesn't happen when supporting the methylation cycle via the enzyme BHMT). The main white cells activated would be T cells. Maybe, and I have not evidence of this, by helping in the formation of T cells we are allowing also the replication of XMRV (known to infect T cells), therefore getting worse by a exacerbation of this infection (providing that I am XMRV+ and that XMRV, indeed, plays a role--other than opportunistic infection-- in the pathogenesis of CFS...).

    If this were true, then I'd need an explanation for as why I feel as bad also taking direct chelators... ;-)

    Just my thoughts!

    Saluditos,
    Sergio
  9. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Hi Tiny,

    This is a reply from Nitekitty (she was unable to log in today) -- she asked me to paste it in here for you. Also, if you would like to reply to her by email, PM me and I'll give you her email:

    "First off, I'm very sorry to hear about your daughter's birth defect due to the polymorphism. I'm lucky in that I did not have children yet (and now I may not be able to because there is no treatment for my polymorphism currently).


    Secondly, yes I know all about the MTHFR polymorphism and the different homocysteine problems. If you would like, I can put you in touch with the leading researchers in homocysteine and MTHFR, Dr Harvey Mudd (NIH) and Dr Conrad Wagner (Vanderbilt). They are really smart guys and have been incredibly helpful. They may be able to come up with a proper treatment plan taylored for you in which they can share and discuss with your general practioner.


    Your polymorphism has much more research on it than mine and it should be much easier to help create a good plan to lower the homocysteine, etc. I am the first documented case of my polymorphism and it is currently being figured out via DNA sequencing. The low betaine has resulted from two genetic anamolies. First--- one of my choline transporters only works at 20 to 30 percent normal capacity so phosphatidylcholine cannot be transported into the mitochondria to create choline (which then creates betaine) and then it cannot effeciently transport enough choline out of the mitochondria for further use once it is created. Second--- I have a choline dehydrogenase defect. My body does not create enough of it to form betaine from choline.

    What results is a deficit of choline, then a deficit of betaine, and then my homocysteine level escalates.

    (That particular choline transporter problem had not been seen in humans until me and no one has been documented with a betaine deficiency yet besides me. So I'm a pretty hard case because there is no precedent for treatment. You will probably be luckier because there has been research on MTHFR.)

    Best wishes,
    Nitekitty (Gen)"
  10. richvank

    richvank Senior Member

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    To Nitekitty.

    Hi, Gen.

    Since both choline and betaine are available as supplements, it would seem that you could supplement them. Are these researchers advising you to do that?

    Best regards,

    Rich
  11. nitekitty

    nitekitty

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    Rich,
    Since choline itself is not well absorbed (and that is data collected via Dr Zeisel at University of North Carolina), phosphatidylcholine is the supplement version of choline. We have pumped me with as much phosphatidylcholine as possible, however if the transporter won't pick it up, it just won't pick it up. And then even if it did, the choline dehydrogenase defect makes it so there is not enough of that enzyme to create betaine from choline anyway.

    So pumping me with quite enormous doses of phosphatidylcholine made my choline go from 3 to 5 basically. It helped a tiny bit (and at my low levels ANY increase is a good one) but it does not quite do the trick.

    As for the betaine supplementation we've come across a peculiar road block that is not fully understood yet. If I am supplemented with enough betaine like a normal human being, my SAM-e levels skyrocket like you wouldn't believe. We're talking tens to even hundreds of times higher than normal. You would think if I was given what I am deficient in that all would go normal but no. We even tried just waiting it out for several months to see if my body cycles would even out, but alas no.

    Interestingly, they plan to do a brain MRS (magnetic resonance spectroscopy) on me tomorrow. This will measure different metabolites in my brain like choline, etc etc. It will be incredibly interesting to see what this reveals and how my treatment game plan may become better suited to me through that information.

    So right now I'm not close to being fixed anytime soon. But hey, if they can use me for research then I'm totally excited about that because no progress can be made without research.

    I want to say thanks though because I got involved in the methylation cycle research stuff through Sushi and you. I began studying and applying your protocol to my dysautonomia and eventually ended up at an unexpected but nonetheless cool outcome so far.

    Best wishes,
    Gen
  12. richvank

    richvank Senior Member

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    Hi, Gen.

    Thanks for the response.

    Since Dr. Mudd is an authority on methylation balance, he has probably considered this, but it might be possible for you to take phosphatidylethanolamine, which is converted to phosphatidylcholine by a methylation reaction. If you have sky-high SAMe, that reaction should go pretty well. That would at least give you more phos. choline. According to one of Dr. Mudd's papers, which I've read, this reaction may be the number two main methylation reaction in the body, after the synthesis of creatine, which is number one.

    I'm glad to hear that they are going to run a brain MRS on you tomorrow. I hope that they will try to measure the absolute concentrations of the metabolites, rather than simply calculate ratios between them. The latter has been done quite a bit in the past in CFS, because it's easier to do, and the researchers have simply assumed that the creatine level is the same as in normal, healthy people. However, with the partial block in the methylation cycle, I don't believe this is true, because methylation is required to make creatine. Dr. Mudd is well aware of all this, so this probably won't be an issue.

    I'm glad that looking into methylation helped to point you in the right direction. Your case sounds pretty unique, and it's great that the specialists at the NIH are working on it. With the inherited deficiencies you mentioned that you have, I can see why your methylation was dysfunctional. I wonder how many others there might be out there with these same issues.

    I wish you the best in getting to the bottom of this an fixing it!

    Rich
  13. nitekitty

    nitekitty

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    Okay, you have to explain to me why that would be beneficial to take phos ethanolamine as opposed to phos chol. The transporter will not pick up phosphatidylcholine to take it into the mitochondria so I'm not following you. Are you suggesting a way to bypass the transporter to get phos chol into the mitochondria? (side note: the transporter in question is in regard to SLC44A1. The paper on it came out last summer, entitled, "The solute carrier 44A1 is a mitochondrial protein and mediates choline transport" by Bakovic and Michel) Where does phos ethanolamine turn into phos chol?

    The SAM-e sky high can be quite dangerous. It easily results in liver damage which Dr Mudd has seen in another patient with a totally different anamolie that caused high SAM-e. And with me at the levels it was at (we're talking the difference between 35 versus 1900) my liver enzymes were bad. Whether that was because of the SAM-e too high or a virus we'll never be sure, but because they had documented liver damage with the other patient with sky high SAM-e, it's a safe assumption to presume at least some of the liver enzymes going out of whack was in regard to the SAM-e. Dr Mudd and Dr Finkelstein together decided the SAM-e level was too dangerous.

    And side note, it took a ridiculous amount of SAM-e to start to elevate the SAH. It was as if the SAM-e would keep escalating and stop right there. Little of it would be passed further on down the cycle. It just kept building up.
  14. richvank

    richvank Senior Member

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    Hi, Gen.

    You have probably the world's most knowlegeable people about this part of the biochemistry working on your case. I, on the other hand, am an amateur. So you probably shouldn't pay too much attention to my comments! :)-)

    You have got me interested, though, so I have today done some homework, reading papers mostly authored by the people you are working with or have mentioned.

    As I understand what you have reported, you have two known polymorphisms (or mutations) in this part of the biochemistry: one in the choline transporter SLC44A1, and one in the mitochondrial enzyme choline dehydrogenase (CHDH). Both interfere with the activity of these proteins, so that the transport of choline into the mitochondria is inhibited, as is the conversion of choline to betaine. The result was that your betaine level was low, thus lowering the activity of the BHMT enzyme in your liver and kidney cells and causing the homocysteine level in your blood to rise to 45 micromoles per liter, well above the normal range.

    As I understand it, because your cells were not able to transport choline well, your doctors decided to try supplementing with phosphatidylcholine, hoping that it would be transported into the mitochondria, break down to form choline, and supply that to the choline dehydrogenase enzyme. Is that right? You wrote that choline is not well absorbed, so that phosphatidylcholine is the supplement form. As far as I know, this is not generally true. Choline supplements include choline chloride, choline citrate, choline bitartrate, and phosphatidylcholine. Lecithin contains phosphatidylcholine, and has been used as a choline supplement. As far as I am aware, these forms are all readily absorbed by most people, so I'm guessing that it is your transporter polymorphism that led to the choice of phosphatidylcholine as the choline form in your case.

    As I understand it, some choline is normally oxidized to form betaine by the enzyme choline dehydrogenase, located in the mitochondria, and then the betaine is exported to the cytosol of the cells, where the BHMT (betaine homocysteine methyltransferase) reaction takes place to convert homocysteine to methionine. This is not happening very much in your case, for two reasons: the choline can't get into the mitochondria very well, and it can't get converted to betaine very well, either.

    If I have this right, so far, then I can understand why supplementing with choline would not be effective in your case. However, it does seem as though supplementing with betaine (TMG) would be helpful. You reported that dosages higher than 1,000 mg of TMG did decrease your homocysteine level, but this caused your SAMe level to rise to tens to hundreds of times normal, which may have been responsible for increasing your liver enzyme levels. Meanwhile your SAH level rose only slightly.

    This causes me to wonder if there is a problem with your glycine N-methyl transferase (GNMT) enzyme. Normally, this enzyme prevents the ratio of SAMe to SAH from going too high, by transferring methyl groups to glycine, forming sarcosine. The sarcosine reacts to form 5, 10-methylene tetrahydrofolate in the folate metabolism. I'm also wondering why some of the other methyltransferase reactions, such as the one that makes creatine, or others of the 50 to 100 known methyltransferase reactions, didn't accept methyl groups, limiting SAMe and bringing SAH up. This is very puzzling. I'm glad you have some smart people looking at it! :)-)

    I now understand that the suggestion I made earlier, to supplement with phosphatidylethanolamine, will not help to raise betaine. Most of the reactions of phosphatidylethanolamine to form phosphatidylcholine, catalyzed by PEMT (phosphatidylethanolamine N-methyl transferase) occur in the endoplasmic reticulum and in a membrane associated with the mitochondria, but not inside the mitochondria themselves. So this would not deliver phos. choline to the mitochondria, let alone raise betaine. So that's a non-starter. Sorry about that.

    I hope they get this figured out, as I'm sure you really do, too! I'll be interested to hear how your MRS scan came out.

    Best regards.

    Rich

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