High Figlu despite high dose MTHF, why?

[kyzcreig]

5-Formyl-THF and Folinic acid (same substance but measured in different places) are low so I've added folinic acid to my daily regiment.
THF and Active Folate are low despite supplementing with high doses of MTHF. Rich Vank suggests it might have to do with high sarcosine, which I do have. Sarcosine can methylate THF:
http://forums.phoenixrising.me/inde...hylation-panel-figlu-cysteine-nagalase.10998/

Sarcosine can be generated by GNMT enzyme activity, whose purpose is to normalize Methionine levels (mine are high):

Which would explain low SAMe and high SAH. Rich Vank thinks this means there's too many methyl groups in the system, and that supplementing with hydroxocobalamin would help pace this better. I do better on hydroxy, definitely. I supplement with Glycine because it's come up low in previous amino acid tests. I find it calming but I would cut it out if needed, my only reservation is that would affect GSH levels. Genova doesn't provide much insight on high sarcosine:

My problems started when I began taking Accutane. Vitamin A and its derivatives (accutane) upregulate GNMT activity.
http://forums.phoenixrising.me/inde...-block-and-glycine-n-methyltransferase.26042/
http://jn.nutrition.org/content/132/3/365.short

I hope this is not a permanent epigenetic issue. Thoughts?

Any advice is welcome. I couldn't find a viable way to downregulate GNMT besides avoiding Glycine, but this seems bad because it will lower GSH levels and keep Methionine high. I found some studies that suggest 5 methyltetrahydrofolate monoglutamate and 5 methyltetrahydrofolate pentaglutamate are strong inhibitors but they are deconjugated in the gut and there are no sublingual supplements available.

 

[Eastman]

I found some studies that suggest 5 methyltetrahydrofolate monoglutamate and 5 methyltetrahydrofolate pentaglutamate are strong inhibitors but they are deconjugated in the gut and there are no sublingual supplements available.

Wouldn't the body convert some MTHF to the polyglutamate form anyway? I think that is how it is stored in the body. Unless something in particular is blocking that conversion.

 

[alicec]

Wouldn't the body convert some MTHF to the polyglutamate form anyway? I think that is how it is stored in the body.

All folate forms within the cell are polyglutamated to some extent. This is what keeps them inside the cell. Folate in the blood is monoglutamated.

 

[Eastman]

All folate forms within the cell are polyglutamated to some extent. This is what keeps them inside the cell. Folate in the blood is monoglutamated.

Which implies that there should not be a concern with them being deconjugated in the gut. The high dose MTHF by kyzcreig should still be inhibiting GNMT.

That still leaves the question of why sarcosine is high despite the high dose MTHF, and how much that contributes to high FIGLU.

 

[alicec]

there should not be a concern with them being deconjugated in the gut

Folate in foods is polyglutamated and the polyglutamate tail is removed in the gut.

The monoglutamated forms in the blood (whether of dietary or supplemental origin) are polyglutamated again once inside the cell.

I don't think this is relevant to the question, nor does the situation described seem to be analogous to that described by Rich in the linked thread. There SAMe was high and this is what made Rich think that the methyl cycle may be overdriven.

The results of @kyzcreig suggest to me that the MTR reaction may not be proceeding well, that excess methyl groups are not the problem.

High figlu suggests limited THF which is produced from MeTHF by MTR. High met would be consistent with slowness at this step. Low RBC MeTHF despite supplementation suggests there could be a problem with it entering cells and so being available to MTR.

High sarcosine is consistent with low THF.

 

[Eastman]

I don't think this is relevant to the question...

This was more or less what I thought.

...nor does the situation described seem to be analogous to that described by Rich in the linked thread.

I assume that kyzcreig linked to the thread because it explained some mechanisms relevant to his situation and not because they are analogous.

The results of @kyzcreig suggest to me that the MTR reaction may not be proceeding well, that excess methyl groups are not the problem.

High figlu suggests limited THF which is produced from MeTHF by MTR. High met would be consistent with slowness at this step. Low RBC MeTHF despite supplementation suggests there could be a problem with it entering cells and so being available to MTR.

High sarcosine is consistent with low THF.

As I understand kyzcreig's approach, he was trying to inhibit GNMT activity to reduce sarcosine, which was thought to be limiting the availability of THF by methylating it.

MTHF, which he was already taking high doses of, is supposed to inhibit GNMT. But you suggest that there may be problem with it entering cells.

Maybe that's where the solution lies.

 

[kyzcreig]

Folate in foods is polyglutamated and the polyglutamate tail is removed in the gut.

The monoglutamated forms in the blood (whether of dietary or supplemental origin) are polyglutamated again once inside the cell.

I don't think this is relevant to the question, nor does the situation described seem to be analogous to that described by Rich in the linked thread. There SAMe was high and this is what made Rich think that the methyl cycle may be overdriven.

The results of @kyzcreig suggest to me that the MTR reaction may not be proceeding well, that excess methyl groups are not the problem.

High figlu suggests limited THF which is produced from MeTHF by MTR. High met would be consistent with slowness at this step. Low RBC MeTHF despite supplementation suggests there could be a problem with it entering cells and so being available to MTR.

High sarcosine is consistent with low THF.

I've read about folate cellular transport but don't remember any actionable conclusions. I have high serum folate so this would be consistent. Do you have any ideas on what to try/research?

For MTR, why would sluggish activity result in high methionine, wouldn't methionine levels depend on the MAT enzymes?

What can I do to ramp up MTR activity, I take plenty of B12. I'm switching fully to hydroxyB12 now to test my theory (and I do better on it normally).


Edit: Interestingly folate uptake in the intestines depends on an outward pH gradient, so not having an alkaline intestine would impede uptake: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC424271/

 

[alicec]

For MTR, why would sluggish activity result in high methionine, wouldn't methionine levels depend on the MAT enzymes?

Sorry, I wrote that when I was very tired. Later I thought something I said doesn't make sense!

That was it - I was thinking of something else - ignore.

Looking at your results again and re-reading Rich's comments in the linked thread, there does seem to be some upregulation of GNMT which has achieved the desired effect - namely driving SAMe down to a normal level (assuming it would otherwise have been elevated along with its precursor methionine).

This is a normal part of the dynamic regulation of methylation reactions and you know that your feedback regulation reactions here are working.

Restricting glycine might have some influence on the reaction but essentially it is driven by other things. Also as you note it could adversely affect the glutathione pathway which is already a problem for you.

Stimulating transsulfuration could be a useful thing to try (B6 plus magnesium). This may improve glutathione status and reduce pressure on MTR by draining homocysteine.

Do you have any results which suggest low transsulfuration (apart from low GSH) - homocysteine or cystathionine?

To me though the outstanding thing about your results that differs a bit from the situation Rich was talking about is the low active folate. In his scenario this should be normal, if not high.

There could be problems with uptake and also recycling of Mefolate - ie the latter may be inefficient, a lot of spinning wheels and wastage.

Personally I'd look to folate before I started trying hydroxyB12. The good result for 10 formylTHF suggests that the MTHFD-related aspects of the folate pathway are working well so I don't see any advantage to supplementing folinic, though who knows, perhaps something unexpected could happen (note though that some people react adversely to folinic).

The reason folinic is suggested is because it can feed all aspects of the folate cycle whereas methylfolate can only enter the wider cycle after reacting with MTR. In your case the non-MTHFR related reactions seem to be ok. This suggests methylfolate is preferred (maybe folinic is lowish because it's being drained to try an supply MTHFR).

I don't know of anything that would improve uptake into cells apart from increasing dose.

You could also look to things that improve the efficiency of the MTHFR reaction, most notably stimulating formation of active B2. This can be much more difficult than just supplying riboflavin. This thread discusses some ideas about how to do that (you need to get into the thread a bit).

 

[Tunguska]

T3 offsets the upregulation by retinoic acid of GNMT: http://jn.nutrition.org/content/134/11/2913.full and it ties in with vitamin A/retinoic acid metabolism frequently in general.

I personally no longer believe methylation cycle explains the more permanent accutane side effects, only some of the ones during treatment, such that the amount of time elapsed since your "treatment" would matter. [if your clinical issues mostly stem from accutane that is]

 

[Justin30]

5-Formyl-THF and Folinic acid (same substance but measured in different places) are low so I've added folinic acid to my daily regiment.
THF and Active Folate are low despite supplementing with high doses of MTHF. Rich Vank suggests it might have to do with high sarcosine, which I do have. Sarcosine can methylate THF:
http://forums.phoenixrising.me/inde...hylation-panel-figlu-cysteine-nagalase.10998/

Sarcosine can be generated by GNMT enzyme activity, whose purpose is to normalize Methionine levels (mine are high):

Which would explain low SAMe and high SAH. Rich Vank thinks this means there's too many methyl groups in the system, and that supplementing with hydroxocobalamin would help pace this better. I do better on hydroxy, definitely. I supplement with Glycine because it's come up low in previous amino acid tests. I find it calming but I would cut it out if needed, my only reservation is that would affect GSH levels. Genova doesn't provide much insight on high sarcosine:

My problems started when I began taking Accutane. Vitamin A and its derivatives (accutane) upregulate GNMT activity.
http://forums.phoenixrising.me/inde...-block-and-glycine-n-methyltransferase.26042/
http://jn.nutrition.org/content/132/3/365.short

I hope this is not a permanent epigenetic issue. Thoughts?

Any advice is welcome. I couldn't find a viable way to downregulate GNMT besides avoiding Glycine, but this seems bad because it will lower GSH levels and keep Methionine high. I found some studies that suggest 5 methyltetrahydrofolate monoglutamate and 5 methyltetrahydrofolate pentaglutamate are strong inhibitors but they are deconjugated in the gut and there are no sublingual supplements available.

Just curious what is the name of the test you are using I can see its a Nutraeval but from which company. Any info would be appreciated.

Was it done at home or by an ND and was it expensive?

Thank you

 

[Izola]

kyzcreig :
My problems started when I began taking Accutane. Vitamin A and its derivatives (accutane) upregulate GNMT activity."

***
kyzcreig:

If you have not already, perhaps you might want to look at the potential risks of Accutane

"Accutane (isotretinoin) is a popular drug for severe acne created by Hoffmann-LaRoche Inc. The drug is linked to severe bowel disease and other side effects. . ." //www.drugwatch.com/accutane/

 

[Izola]

5-Formyl-THF and Folinic acid (same substance but measured in different places) are low so I've added folinic acid to my daily regiment.
THF and Active Folate are low despite supplementing with high doses of MTHF. . . .
* * *

My problems started when I began taking Accutane. Vitamin A and its derivatives (accutane) upregulate GNMT activity.
http://forums.phoenixrising.me/inde...-block-and-glycine-n-methyltransferase.26042/
http://jn.nutrition.org/content/132/3/365.short

I hope this is not a permanent epigenetic issue. Thoughts?

Any advice is welcome. I couldn't find a viable way to downregulate GNMT besides avoiding Glycine, but this seems bad because it will lower GSH levels and keep Methionine high. I found some studies that suggest 5 methyltetrahydrofolate monoglutamate and 5 methyltetrahydrofolate pentaglutamate are strong inhibitors but they are deconjugated in the gut and there are no sublingual supplements available.

* * * *
kyzcreig:
If you have not already, perhaps you might want to look at the potential risks of Accutane

"Accutane (isotretinoin) is a popular drug for severe acne created by Hoffmann-LaRoche Inc. The drug is linked to severe bowel disease and other side effects. . ." //www.drugwatch.com/accutane/
iz

 

[kyzcreig]

Do you have any results which suggest low transsulfuration (apart from low GSH) - homocysteine or cystathionine?

To me though the outstanding thing about your results that differs a bit from the situation Rich was talking about is the low active folate. In his scenario this should be normal, if not high.

There could be problems with uptake and also recycling of Mefolate - ie the latter may be inefficient, a lot of spinning wheels and wastage.

Personally I'd look to folate before I started trying hydroxyB12. The good result for 10 formylTHF suggests that the MTHFD-related aspects of the folate pathway are working well so I don't see any advantage to supplementing folinic, though who knows, perhaps something unexpected could happen (note though that some people react adversely to folinic).

The reason folinic is suggested is because it can feed all aspects of the folate cycle whereas methylfolate can only enter the wider cycle after reacting with MTR. In your case the non-MTHFR related reactions seem to be ok. This suggests methylfolate is preferred (maybe folinic is lowish because it's being drained to try an supply MTHFR).

I don't know of anything that would improve uptake into cells apart from increasing dose.

You could also look to things that improve the efficiency of the MTHFR reaction, most notably stimulating formation of active B2. This can be much more difficult than just supplying riboflavin. This thread discusses some ideas about how to do that (you need to get into the thread a bit).

I do have low Cysteine on my Amino Acids test. But I have high sulfates, so I'm wondering if there's an issue with the CDO enzyme. Or if the sulfates could be caused by something else. I don't feel well if I take cysteine or thiol supplements in general, except glutathione, but even too much of that is not good.

T3 offsets the upregulation by retinoic acid of GNMT: http://jn.nutrition.org/content/134/11/2913.full and it ties in with vitamin A/retinoic acid metabolism frequently in general.

I personally no longer believe methylation cycle explains the more permanent accutane side effects, only some of the ones during treatment, such that the amount of time elapsed since your "treatment" would matter. [if your clinical issues mostly stem from accutane that is]

Interesting, thank you. I agree, the Accutane is probably long gone out of my system. I have a strong hunch if I corrected the glutathione and methylation it would either resolve all my issues or lead to a root issue.

Just curious what is the name of the test you are using I can see its a Nutraeval but from which company. Any info would be appreciated.

Was it done at home or by an ND and was it expensive?

Genova Diagnostics ION with 40 amino acids
HDRI Methylation Pathway