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HELPS - Supplements for hetero a1298C?

Discussion in 'Genetic Testing and SNPs' started by dan132, Jun 16, 2016.

  1. dan132

    dan132

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    Hello everyone :)

    This is my first post on this site!

    I recently found that I have the MTHFR a1298c Heterozygous mutation.
    I believe this to be the cause of all of my symptoms which are basically, demotivation, anhedonia, poor focus/concentration, and just feeling generally un-enthused with life.

    I can't seem to find much CLEAR info about what supplements I should be taking for this particular mutation (1298). Should I be taking L-MTHF or Folinic Acid (Calcium Folinate) and how much?
    Same goes for B12, do I need MethylB12? HydroxyB12? AdenB12?
    What other supplements should I consider? (If only I could get me some BH4 in Australia)

    I have had brief periods of success where I feel absolutely epic (full of life, enthused, energetic, able to focus and happy) with 1000mcg HydroxyB12 (first thing in morning), 400mcg L-MTHF 3x day (every 6hrs) and 300mg N-A-Tyrosine 2x day (with the first two MTHFs)... However I can never get the feelings to last, I feel good for a day or two at most, then gradually the benefits I was feeling start to get less and less (over about a week) until I feel the supps are no longer doing anything at all :/

    Have currently stopped taking anything for a week so that I can start back up again, but unsure what I will do differently to try maintain the good feeling?

    Am I on the right track at all???? What could I do differently?
    Any help would be greatly appreciated :)

    Many Thanks

    Daniel :)
     
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  2. alicec

    alicec Senior Member

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    That variant, even in +/+ form, causes only a small slowing of the enzyme. It would most definitely NOT be the cause of your health problems.

    Unfortunately you have been bamboozled by the inaccurate claims and myths started by Yasko and repeated by many others.

    Her claims that this variant affects the backwards reaction of the enzyme which in turn is involved in regeneration of BH4 (which in turn is involved in neurotransmitter production) is simply nonsense based on a complete misreading of research.

    The enzyme does not run backwards and it does not regenerate BH4.

    Methylfolate can act as a peroxynitrile scavenger and so have a BH4 sparing effect, but +/- A1298C would have only a very small influence on methylfolate levels (if any).
     
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  3. Critterina

    Critterina Senior Member

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    Hi @dan132 ! Welcome to the forum!

    As I'm sure you'll notice, if you've been reading around, there are a variety of opinions here. We don't agree with each other, and many of us (like @alicec above) don't agree with Yasko. So let me offer my opinion, and let you make the most of your ability to put it all together and figure it out.

    I'm also hetero A1298C. I was known as "a melancholy child" and have had three significant episodes of depression as an adult (and also many minor ones). I know what ahedonism is, by experience. And although I was way sick, beyond anhedonism or depression when I was diagnosed and prescribed MTHF and B12, I think those have been part of my recovery.

    Regarding A1298C, I agree that Yasko misread the research, that the reaction probably doesn't run backwards as she says, but that it does spare BH4, just as if the reaction ran backwards. It's also statistically associated with all the symptoms and, I would guess, the relief that you feel temporarily when you supplement.

    Regarding folinic acid - so tempting because it's so cheap - I think it's probably a trial and error thing. If the reaction did run backwards, it would explain the BH4 sparing. If the reaction doesn't run backwards, does it inhibit BH4 sparing? I don't know, all I know is I don't tolerate it; the effect is just short of narcolepsy. But some people with our same mutation tolerate it, and some don't but have other symptoms.

    I don't know why your benefits peter out after about a week. One explanation you hear a lot around here is that you've used up something else. It used to be that the thing you are taking (folate or B12) was the rate-limiting step, but now that you have enough of that, the chemical reactions run to the point that something else is the bottleneck, so to speak.

    In that regard, I like to get enough of the other B vitamins and some of the common alkali metals and alkaline earth metals: sodium (salt, probably the least important for most people), potassium (coconut water has 3x what bananas do), magnesium (as a Mg glycinate supplement or as Epsom salt baths), and calcium (but I'm Nordic and use a lot of dairy products, so I don't supplement past that.) The active B multi that I like is B-Healthy! or B Healthy. One is by Answers from Nature (my fav), the other is by Emerald Laboratories (also very good by my experience).

    Another thought is that you are only taking the MB12 once a day. It doesn't stay in the body for long; I take it twice a day, but I'm better if it's 3x. I use Costco's, 5000 mcg - but shop carefully as they also have the cyano form.

    So, as my doctor told me last week about something else that's bothered me since childhood, science hasn't caught up with this yet.

    Oh, another thought (they come to me every so often) is that I found a serum amino acid profile very helpful. You take tyrosine - one of the neurotransmitter precursors. I'm always good in that. But even taking tryptophan, the other neurotransmitter precursor, I'm always low. Both of those are converted by BH4, by the way. And taking that (tryptophan) with the Bs seems to help. I bought some BH4 ($80!) and I didn't notice a thing! Also, based only on the idea that since NutraHacker analysis showed that 10 of my top 100 SNPs indicated I could probably benefit from Lithium, I used 5 mg Lithium Orotate for about a year. It made a huge difference in my mood until all of a sudden I didn't tolerate it!

    So, I wish you the best. You aren't me and I wouldn't expect what worked for me to work for you. But you didn't list "brain fog" so having your mind work (unmotivated though you may be) will be your biggest help. Listen to everybody and see what makes sense. Then take good notes on what you try, so you can go back and look for cause and effect. Also, if you can get a doctor or nurse practitioner to help, that's a good investment in yourself!

    Critterina
     
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  4. lnester7

    lnester7 Seven

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    I thoguht I was the only one, I go to sleep w brain inflammation for days!!!! I cannot tolerate folinic/folic acid
     
  5. Critterina

    Critterina Senior Member

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    Oh, I didn't think it was brain inflammation, but about 20 minutes after, I have to fight to stay awake. It's over in an hour or so.
    I am starting to suspect that the swelling in the seams of my skull and the hard pinching inside my head on my ear canals may have been brain inflammation - from histamine intolerance. I am SO much better on that front now.
     
  6. dan132

    dan132

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    Thanks guys for the responses so far!

    Alicec, I also was following that train of thought at one stage, but I simply cannot argue with the results I see for that brief period when I feel amazing... Whatever the mechanism causing me to feel so back to normal must be maintainable, surely..?

    Critterina, Oh woops, I DEFFINITELY did have brainfog! That was the first and most debilitating symptom I noticed while still studying in University. It was so bad that I almost dropped out. But now that I'm done with my studies I am just trying to get my health in check before I launch myself into a career, and I think it is just harder to notice the brainfog because I'm not having to do any/much mental problem solving as I was before.
    About the B12, I was feeling good using the HydroxyB12 rather than the Methylb12. Another thing I kind of don't understand is why I need to take b12 at all? Doesn't the MTHFR mutation itself only hinder the product of MTHF? Or does it also affect b12? Is it possible that I don't even need the b12?
    Because technically shouldn't correcting the faulty gene by added in some MTHF be all that I need? I have seen some people on here who take a crazy huge list of supplements which to me doesn't make a whole lot of sense when the gene only affects MTHF, Shouldn't the body be doing all the rest itself?

    About the Folinic Acid (which I believe is only one step away from being MTHF), is the MTHFR gene required for this final step in the conversion??

    Thank again for all your input guyzz

    :)
     
  7. Critterina

    Critterina Senior Member

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    @dan132 ,

    Well, I'd say you're doing pretty well for brain fog! Keep up the good work. This will definitely give you some practice at problem solving. As far as I can see, you're asking all the right questions. Now if we only had answers.... :p

    About the B12, you're right. It's very likely you don't need it. Now there's an experiment for you. Maybe the next time you try your supplements, you could leave out the B12.

    The C677T MTHFR mutation affects the conversion of folinic acid to methylfolate - but you don't have that reaction, so theoretically, you shouldn't need to take methylfolate and could get by on folinic acid. This would be particularly true, theoretically, if the reaction doesn't go backward (e.g. Yasko's wrong, which we think she is). But much evidence is to the contrary - that people with the A1298C mutation report being much improved taking methylfolate, myself included. We don't know why. As a separate experiment, you could try the folinic acid instead of folate. See what happens.

    So, why the B12? To use up methylfolate in the methyl cycle, you need to activate the MTR enzyme, and to do that you need an active (methyl B12) in the MTRR enzyme. Do you have enough of it? Maybe so. Can you activate (methylate) the B12 yourself? Well, since you did well with the hydroxyB12, very likely you can. If so, you get a nice steady supply of methylB12 by taking the hydroxy form - if you even need to supplement it. (I, on the other hand, have a homozygous mutation of the MTRR in the location known to have the most adverse effect on the methylation of B12, the A644A, so I use methylB12. BTW, I also have the most adverse homozygous mutation on the BHMT-08, which is a second methyl cycle pathway. Both pathways convert homocysteine to methionine. Now, the BHMT-08 is not a very severe adverse mutation, but since I have mutations in all the enzymes that help convert homocysteine to methionine, I figure I should supplement something in there, and I choose B12.)

    Have a good evening!
     
  8. alicec

    alicec Senior Member

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    There have been extensive genome wide association studies involving many thousands of people trying to define SNPs associated with depression. Here is one example and here is the conclusion.

    MTHFR didn't even make the list of possibles worthy of further investigation, and that is the entire gene, let alone a single SNP.

    It is not a question of one's opinion of Yasko, it is a question of looking at the evidence. Her statements about this SNP are not based on any scientific studies and in fact are contradicted by them.

    The SNP is very common so it is hardly surprising that it turns up in people with depression - also very common. there is not a shred of evidence that there is any causal link.

    The fact that methylfolate and B12 have been helpful in your recovery doesn't point to this SNP being the reason for the effect. Plenty of people without the SNP are also helped by these vitamins - and vice versa.

    Methylation pathways have wide impacts, including on neurotransmitter production. It is hardly surprising that stimulating these pathways in a population where metabolic derangements seem to be the norm, ie the ME/CFS population, often seems to have beneficial effects.

    @dan132 I suggest it is the same general mechanism that has benefitted you. If indeed it were the simple direct link between a SNP and your condition, then the methylfolate supplement would continue to work and be the solution to your problems.

    Instead you are experiencing the complexity of intersecting metabolic pathways and feedback inhibition.
     
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  9. alicec

    alicec Senior Member

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    Neither of these statements is correct.

    Folinic acid is a storage form of folate. It is not on a pathway to anywhere else, nor is it the form of folate in vegetables, as is commonly believed.

    Folinic acid is 5 Formyl THF. It is formed as a side reaction from 5,10 Methenyl THF by the action of the MTHFS enzyme. This is a reversible reaction, with the enzyme SHMT1 catalysing the conversion back to 5,10 Methenyl THF.

    The latter compound is on the pathway between THF and MeTHF but is still two steps away. The enzyme MTHFD1 converts it to 5,10 Methenylene THF, and this is the substrate for MTHFR, which converts this new substance to MeTHF.

    Both MTHFR SNPs, ie C677T and A1298C, act in the same way - they slow the reaction forming MeTHF from 5,10 Methenylene THF, though the latter SNP has less effect than the former.

    I'll upload an illustration of this part of the pathway. Please note that even though this diagram includes far more detail than Yasko's (incorrect) version, this is still only part of the folate cycle. It is very complex.

    Some people do well on folinic supplementation, some react badly. The reasons for this are unknown but presumably it has something to do with difficulties in processing folinic, and therefore possibly with the two enzymes which act on it, MTHFS or SHMT1. Accumulation of folinic will act to inhibit other pathways and so there could be a cascading effect.

    As I mentioned above, this SNP acts in the same way as C677T, it slows (slightly) the MTHFR enzyme. This reaction has nothing to do with BH4, it simply forms MeTHF from 5,10 Methenylene THF.

    Yasko didn't just misunderstand about the reaction running backwards, she totally misunderstood the study. BH4 is not part of this reaction in any way - there is NO direct link between MeTHF and BH4.

    In my earlier post I was trying to be comprehensive in showing how MeTHF might have an indirect BH4-sparing effect by scavenging peroxynitrile.
     

    Attached Files:

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  10. Critterina

    Critterina Senior Member

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    @alicec ,

    That's a great picture - much more informative than the paragraphs above it. I always wondered about when I read that 5-formyl and 5,10-methenyl were the same thing - that shouldn't have been so, I thought, and you're saying it isn't. It also shows 5 steps, not 4, from DTHF to MTHF.

    Hearing your conviction about lack of identification of a specific single gene to depression brought me back to 1981 in my biochemistry class. It had been approximately 40 years since the food industry had been hydrolyzing oils to make margarine. It was odd to think that all those stiff bonds in the fatty acids would not affect the cell wall properties, which were otherwise made of carbon chains that freely rotated their entire length. But all research to date said that it didn't.

    There is a genetic disorder in my family that causes multiple endocrine tumors. It's not the MEN1 that is known to be associated with multiple endocrine tumors, but the doctors still think it's genetic. There's another genetic disorder that I have, and my specialist has finally, only 2 weeks before my 57th birthday, finally ordered the first test to explorethe cause, not that he would be comfortable treating it, but with no data, I can do nothing towards pursuing treatment. In his words, "Science hasn't caught up with you yet."

    Tell me what I'm missing here: http://www.ncbi.nlm.nih.gov/pubmed/21550412 among lots of ncbi articles that agree with it.
     
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  11. Critterina

    Critterina Senior Member

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    Obviously you understand where this diagram is lacking. Can you please annotate or elucidate? Are there 6 steps, not 5 from DHF to MTHF? Cofactors missing? Complete arms of reactions missing? Thanks.
     
  12. alicec

    alicec Senior Member

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    I'm sorry - I don't understand the significance of this comment.

    The article is talking about the role of the enzyme DHFR in regeneration of BH4, one of two enzymes which can fulfil this role (the other is DHPR, dihydropteridine reductase).

    I was talking about the claim by Yasko that MeTHF directly regenerates BH4 (when the MTHFR enzyme runs backwards) and said that it doesn't, that there is no direct link.

    The paper you cite doesn't in anyway contradict this. It shows that an enzyme (DHFR) that functions in the folate pathway is also involved in BH4 regeneration, it doesn't show that MeTHF/MTHFR is responsible.

    Regeneration of BH4 and formation of THF are two separate events that happen to use the same enzyme. Regeneration of BH4 isn't dependant on the folate cycle or vice versa.

    The reason these two events use the same enzyme is that biopterin and folate are closely related, both being pteridine derivatives. The enzyme DHFR has sufficiently broad specificity that it can recognise both substances. (This breadth of specificity also means that the enzyme can recognise folic acid, even though this compound is unknown in nature). Once either substrate is engaged, the enzyme acts with the same mechanism to reduce it.

    DHPR is fussier with its substrate and doesn't act on folate, only biopterin.

    Yes. The totality of folate reactions is so complex that some part is usually abbreviated in order to clarify the part that any particular study is trying to illuminate.

    Here is another diagram which shows pathways branching off 10 formyl THF which were missing in the other diagram (though indicated by an arrow to purines), as well as another pathway going directly from THF to 5,10 methylene THF (glycine cleavage system).

    Here is an alternative diagram showing that different reactions happen in different parts of the cell.
     
    Last edited: Jun 19, 2016
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  13. renerdrat

    renerdrat Every teardrop is a waterfall

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    Hey OP I'm also hetero. I found for me what has helped significantly is taking a lot of methylfolate 10mg, b12 2500mcg and b6 I take about 250mg. This seems like a lot .. and I can have some "detox" feelings if you will, more feelings of apathy but then I start to feel good as long as I keep my diet clean and don't drink... which is hard for me. I have a bad problem binge drinking. For a while I was only incorporating methyl folate and not enough b6 or b12, but for me I felt much better when I added them all together in large amounts.

    I have some other mutations though that I still feel I'm sensitive to certain foods and is confusing. I also have a mutation that means I shouldn't eat foods high in sulfur.
     

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