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Dealing with MTR Mutations

mtr methionine homocysteine methyfolate adenosylcobalamin mtrr a2756g

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#1 Ukko

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Posted 01 April 2017 - 02:02 PM


I have been blessed with two homozygous double mutations on the MTR gene (5-methyltetrahydrofolate-homocysteine-methyltransferase or methionine synthase).

 

One is  rs 1805087 (aka A2756G, for which I am GG) and it seems to be an uregulation that can be quite beneficial, assuming that it gets the raw materials it needs. There is some quite conflicting info about this SNP out there.

 

The other one is rs 2275565 for which I am also double homozygous. I have little information about it, but it seems to be an upregulation also.

 

Now, MTR is of course the thing that revs up your entire methylation cycle. By using methylfolate and methylcobalamin to create methionine from homocysteine. And I have none of the associated nasty MTRR or MTHFR mutations that could complicate things further. So my genetic cocktail is a little weird.

 

Anyhow, given that this mutations are really rare (A2756G GG is like 2% chance only for Europeans), there is little information on the net. The likelihood of having these two homozyguous mutations is less than 0.5%.

 

Here's what I have been trying to do over the recent years:

 

1) supplement 1000mcg - 3000mcg adenosylcobalamin to ensure that the metabolical needs for B12 are taken care of for the ATP cycle despite the MTR using a ton of methylcobalamin. I think they are interconvertable in the body to some degree. But not always, and I want to ensure that the ATP cycle has the B12 it needs despite MTR being on overdrive

 

2) supplement a little with methylcobalamin, but I am not getting good reactions from higher amounts. Likely because the MTR is on overdrive

 

3) supplement with methylfolate to provide the other reagent for MTR. This things is damn expensive though. Cannot afford like 5-15mg doses, though I have tried and thought they were beneficial

 

4) supplement both creatine and lecithin (for phosphatidylcholine) thus lowering the body's need to methyl groups by up to 50%. These are the two processes that use up to 50% of the methyl groups in the form of SAMe in the body.

 

5) supplement TMG and B6 to try to shunt some homocysteine down the the alternative paths

 

People also say that pro-glutathione compounds like NAC and ALA should be avoided. But I have been using them for 25 years with great results. And some people say the exact oppsite. Has something to do with glutathionyl-cobalamin. Haven't looked into that yet.

 

Anyhow, the more I have been thinking about it, the more it seems to me that the really limiting factor for MTR, assuming no MTRR mutations or issues with B12 absorption (intrinsic factor) is actually that damn pricey methylfolate. MTR uses it. And if it is revved up, then it uses more. So I suspect that people like me would generally benefit from methylfolate, adenosylcobalamin, maybe from methylcobalamin and somehow tuning down the MTR a little bit, if possible.

 

Anyone similarly situated or with insights out there? Would appreciate anything. Most of the talk on the other forums is meaningless noise. Most people do not even understand that A2756G is an UPregulation. The MTR works especially well and fast. So sort of a born hypermethylator.


Edited by Ukko, 01 April 2017 - 02:10 PM.

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#2 Andey

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Posted 01 April 2017 - 06:32 PM

You mean polymorphisms, not mutations. Mutations are less then 1% and very unfavorable for survival.

I have C667T homoz., MTR A2756G heteroz., MTRR A66G homoz, BHMT-08 homoz.

I found two people on phoenixrising with similar profile, both mostly bedridden. 

I had my problems too, but I cannot put my finger on that a methylation was a cause of it. At least my homocysteine is at reasonable level even without supplementation and quite good while supplementing.

You situation is different but if I were to give advice I would propose to give a hydroxycobalamin a chance, it could be the the source for both methyl and adeno types and you would not overload you system with it. Supplement with folate (your incerased B12 turnover also increases a folate consumption) but never exceed 800 mcg (it would speedup you methylation even more). B2 is also very important (but what B is not ?). Its also nice idea to try not oral forms of B12 transdermal oils or IM shots, but I would not do that with methylB12, it could be unsafe. In my case glutathione IV was very beneficial (for my particular problem) and very well tolerated. I assume I know guy that started that myth about glutathione is dangerous and generally I think its a BS based on n=1 experience and other ideas from this guy are unsafe (ie hyperloading with B12 and folate)

Anyway you seems more knowledgeable in this area than me. I am here just to break the ice in the thread )

 

I would also suggest to do 23andme test for all people with homocysteine levels out of wack. Knowledgebale supplementation could save from a BIG problems in a future.


Edited by Andey, 01 April 2017 - 06:32 PM.

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#3 Ukko

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Posted 01 April 2017 - 07:31 PM

You mean polymorphisms, not mutations.

 

- Yes, true, that is the correct term. My bad.

 

I have C667T homoz., MTR A2756G heteroz., MTRR A66G homoz, BHMT-08 homoz.

 

- Auch. C677T homozygous must be rough with MTRR A66G homozygous.

 

I found two people on phoenixrising with similar profile, both mostly bedridden. 

 

- No beef with that.

 

 

You situation is different but if I were to give advice I would propose to give a hydroxycobalamin a chance, it could be the the source for both methyl and adeno types and you would not overload you system with it.

 

- Fair point. Need to read up on it. Though the likes of Freddd are not bullish on hydroxycobalamin, to make an understatement. But I´never personally looked into that. And I should. Thank you.

 

 

Supplement with folate (your incerased B12 turnover also increases a folate consumption) but never exceed 800 mcg (it would speedup you methylation even more).

 

- Am inclined to agree, but do you have any data to back that up?

 

B2 is also very important (but what B is not ?).

 

- So very true, agreed.

 

Anyway you seems more knowledgeable in this area than me. I am here just to break the ice in the thread

 

- And thank you for doing that. Highly appreciated. Take care.

 

 

 


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#4 Andey

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Posted 01 April 2017 - 08:22 PM

 

 

 

 

- Am inclined to agree, but do you have any data to back that up?

 

 

 

 

I am mostly repeating ideas from Greg from b12oils who is Phd in this area. If I remember correctly his idea that anything above 800mcg is uncharted territory and one should aware that overspeeding methylation pathways could mean more demand for other pathways that are not supposed to be used that way. Body have huge ability to overcompensate one pathway but one could get into huge trouble when few connected pathways are distorted.

In my experience even with homozygotous C677T even 800mcg of folate is too much. Ive done blood test that supposed to show active folate and b12 levels.

While supplementing 800 mcg and around 3-4 mg of meB12+adenoB12 a day my active folate (folate in rbc) was 10% above range and B12 (holotranscobalamin) was whooping 5 times above range. From that point I cut down dosages to 1mg of b12 a day and havent noticed any adverse difference. 

Now I take 1mg hydroxyB12 sporadically and 400 mcg of folate, on this regimen my homocysteine is about 7-8.5 which is not optimal enough (I believe normal range is up to 12 and ideal level is around 5-6) but quite good for C677T carrier. It was 9 without supplementation which is what should be expected from healthy C667T TT carrier.

 

I would say we still know  very little about methylation genetics. Accordingly to my SNPs I should have very messed up methylation but I am not. I also have homoz. COMT polymorphism that means I should have very low tolerability to extra methyl groups but I havent noticed any adverse effects from high meB12 or SAMe supplementation. And some people jump straight to anxiety while supplementing meB12 and SAMe even without COMT deviations. Go figure )


Edited by Andey, 01 April 2017 - 08:31 PM.

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#5 PeaceAndProsperity

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Posted 01 April 2017 - 11:38 PM

You are trying to explain a lot from a few common genetic defects. Polymorphisms are mutations unless you consider the right genetic material (the way it's supposed to be) to also be under that term, in which case it becomes a "they're not mutually exclusive," it's just a play with words.


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#6 Andey

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Posted 02 April 2017 - 05:05 AM

You are trying to explain a lot from a few common genetic defects. Polymorphisms are mutations unless you consider the right genetic material (the way it's supposed to be) to also be under that term, in which case it becomes a "they're not mutually exclusive," it's just a play with words.

Its not up to us to determine terms and yep 'right genetic material' is also a polymprphism. Its called wild type and its often not possible to determine it when all 3 variants are around 30%, or one variant is often in caucasians and other one in asians.
Mutations are very rare and it usually a sign that people with it could not survive trough childhood and pass their genes further.
Sine is sine, hypotenuse is hypotenuse, polymorfism is polymorfism.

Edited by Andey, 02 April 2017 - 05:07 AM.

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#7 Ukko

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Posted 02 April 2017 - 06:46 PM

You are trying to explain a lot from a few common genetic defects.

 

Well, our gene pool is virtually the same as it was in the cave 10,000 years ago. But our environment is very different. Polymorphisms that were bad back then may be good now and the other way around. As our current lifestyle, nutrition etc. is artifical in light of our ancient genes.

 

Here's a number for you. The rather common C677T polymorphism with the MTHFR gene, if homozygous TT, causes a downregulation of MTHFR expression by about 65-70%. Throw in another common polymorphism in the MTHFR gene, A1298, in the mix in a compound manner and you may be looking at ap to 90% downregulation.

 

This in the MTHFR gene that is very central to methylation and therefore impacts every cell in the body. And even impacts the very DNA expression itself. I would personally not belittle SNPs. If they did not matter, we'd be all almost identical twins :)
 


Edited by Ukko, 02 April 2017 - 06:47 PM.

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Also tagged with one or more of these keywords: mtr, methionine, homocysteine, methyfolate, adenosylcobalamin, mtrr, a2756g

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