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MTHFS defect (folinic acid intolerance) - request for genetic data

nandixon

Senior Member
Messages
1,092
Nandixon, would you by chance have any references for this inhibiting effect of vitamin A on SHMT? I take 25,000 iu of vitamin A daily, and I am +/- for SHMT1 C1420T (my full genotyping results given here). I think I may stop taking vitamin A for a while, to see if this helps with my methylation cycle.

Hi Hip,

I think it's from the book and pages I mentioned, but it doesn't seem to be available from Google anymore, unfortunately:
The book "Nutrient-Gene Interactions in Cancer" gives more detail about all of the above (SHMT & folinic acid). Available as a Google book, pages 218-222 are free.
 

brenda

Senior Member
Messages
2,266
Location
UK
MTHFS, 80136129 rs685487 A or G AA
MTHFS, 80136288 rs8033649 A or C CC
MTHFS, 80137560 rs8923 C or T TT
MTHFS, 80138571 rs2733103 C or T CC
MTHFS, 80138745 rs16971427 A or C AA
MTHFS, 80141997 rs655473 A or G AA
MTHFS, 80144197 rs17284990 C or T TT
MTHFS, 80154571 rs16971450 A or G AG
MTHFS, 80154982 rs6495446 C or T CT
MTHFS, 80158042 rs7177659 A or C CC***
MTHFS, 80158159 rs6495449 A or G GG
MTHFS, 80162265 rs17285431 A or C AA
MTHFS, 80164053 rs6495451 C or T CT
MTHFS, 80165368 rs2586154 A or G GG
MTHFS, 80168282 rs12899781 G or T TT
MTHFS, 80171971 rs16971478 A or G AA
MTHFS, 80172133 rs2586153 C or T CC
MTHFS, 80174388 rs2562744 A or C AC
MTHFS, 80177687 rs2733106 A or G AA
MTHFS, 80178283 rs12438477 A or C AC
MTHFS, 80182050 rs12898642 C or T CT
MTHFS, 80183766 rs2586182 A or C AA
MTHFS, 80184657 rs2733088 A or G AG
MTHFS, 80186340 rs12440798 C or T CC

I took 200mcg folinic acid yesterday and today I have softer skin and a better BM this am. I will take the same dose today and increase it the following day to 400mcg.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
I don't want to get anyone's hopes up, but I spoke to someone who has SHMT C1420T rs1979277 AG and said they got a big boost from folinic the first day and then later experienced fatigue. I assume there's other reasons for methylation to cause fatigue, so we'll see what happens when she stops folinic for a few days. If she does feel better after stopping, hopefully she'll try it one more time just to make sure.

nandixon
I'm confused by the symptoms of folinic acid intolerance. No offense to Freddd, but some of the symptoms he lists for "paradoxical folate deficiency" seem less than clear. For example, he lists IBS as a symptom, but in the methylation study done by Rich and Dr. Nathan on CFS/ME patients, gastrointestinal disturbances was the most common symptom reported by the participants. Also, heart palpitations could be a symptom of overmethylation rather than paradoxical folate deficiency.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
I'm -/- for SHMT. Do I still need to post my MTHFS results? I'm not sure if I have a problem with folinic or not. I've done some tests, but I'm still not sure. I don't have fatigue even when I'm only taking folic acid (and I'm MTHFR). Actually, what I mean is that my wiredness/overstimulation overrides my fatigue so I'm sure there is fatigue underneath. Either way, I don't know how to test folinic. I just started methylfolate. Maybe after awhile I'll have a better idea, but I'm open to suggestions. As I said in my last post, I'm a bit dubious of Freddd's symptom list since some of them are also symptoms of methylation (or overmethylation).
 

nandixon

Senior Member
Messages
1,092
I don't want to get anyone's hopes up, but I spoke to someone who has SHMT C1420T rs1979277 AG and said they got a big boost from folinic the first day and then later experienced fatigue. I assume there's other reasons for methylation to cause fatigue, so we'll see what happens when she stops folinic for a few days. If she does feel better after stopping, hopefully she'll try it one more time just to make sure.

nandixon
I'm confused by the symptoms of folinic acid intolerance. No offense to Freddd, but some of the symptoms he lists for "paradoxical folate deficiency" seem less than clear. For example, he lists IBS as a symptom, but in the methylation study done by Rich and Dr. Nathan on CFS/ME patients, gastrointestinal disturbances was the most common symptom reported by the participants. Also, heart palpitations could be a symptom of overmethylation rather than paradoxical folate deficiency.

Hi Lotus,

Thanks! If the person you mentioned with SHMT1 rs1979277 AG did testing with 23andMe it would be helpful if they could also post their MTHFS results.

I'm only familiar with the seeming intolerance I experienced, i.e., an initial benefit (= less fatigue) the first day with folinic acid but then an exacerbation of fatigue the following days (and some enlarged/irritated taste buds). This was using 800-1600 mcg/day of Source Naturals "MegaFolinic" brand.

I may be wrong, but rather than over-methylation, I think it's more likely that if someone finds folinic acid makes their CFS/ ME symptoms worse, that it may be due to an inhibition of the SHMT (SHMT1) enzyme or one of several other enzymes folinic acid is known to inhibit.

(MTHFS fits in here because if the MTHFS enzyme is not working well, i.e., not doing a good job converting folinic acid to methenyl THF, then too much folinic acid may hang around when that form of folate is supplemented and thus cause inhibition of SHMT or another enzyme. So it may be that when someone has a problem with folinic acid they may have defects in both MTHFS and SHMT1, for example.)
 

nandixon

Senior Member
Messages
1,092
I'm -/- for SHMT. Do I still need to post my MTHFS results? I'm not sure if I have a problem with folinic or not. I've done some tests, but I'm still not sure. I don't have fatigue even when I'm only taking folic acid (and I'm MTHFR). Actually, what I mean is that my wiredness/overstimulation overrides my fatigue so I'm sure there is fatigue underneath. Either way, I don't know how to test folinic. I just started methylfolate. Maybe after awhile I'll have a better idea, but I'm open to suggestions. As I said in my last post, I'm a bit dubious of Freddd's symptom list since some of them are also symptoms of methylation (or overmethylation).

In Lundell's 2006 paper (http://www.ncbi.nlm.nih.gov/pubmed/16889122), the narrowly defined subset of CFS/ ME patients in that study were able to tolerate a regime of 25mg of folinic acid 3-4 times per day, for a total of 75-100mg per day! I wasn't able to tolerate 1mg. Just offhand, I'd say that if you can't tell, for example, whether 4-8mg (= five to ten 800mcg tablets) per day makes your fatigue worse, then you probably don't have a significant intolerance to folinic acid.
 

nandixon

Senior Member
Messages
1,092
For people with CFS/ ME who have done 23andMe testing and would like to contribute to this thread, note that there are ideally three (3) pieces of information to provide:

1. Your reaction to supplementing with folinic acid (not folic acid), i.e., did it make your fatigue worse, better or no change.

2. Your results for the MTHFS gene found here:
https://www.23andme.com/you/explorer/gene/?gene_name=MTHFS

3. Your result for the one SHMT1 SNP found here:
https://www.23andme.com/you/explorer/snp/?snp_name=rs1979277

Note that without knowing your reaction to folinic acid, your MTHFS and SHMT1 results are not really helpful. :)

Thanks!
 

brenda

Senior Member
Messages
2,266
Location
UK
MTHFS, 80136129 rs685487 A or G AA
MTHFS, 80136288 rs8033649 A or C CC
MTHFS, 80137560 rs8923 C or T TT
MTHFS, 80138571 rs2733103 C or T CC
MTHFS, 80138745 rs16971427 A or C AA
MTHFS, 80141997 rs655473 A or G AA
MTHFS, 80144197 rs17284990 C or T TT
MTHFS, 80154571 rs16971450 A or G AG
MTHFS, 80154982 rs6495446 C or T CT
MTHFS, 80158042 rs7177659 A or C CC***
MTHFS, 80158159 rs6495449 A or G GG
MTHFS, 80162265 rs17285431 A or C AA
MTHFS, 80164053 rs6495451 C or T CT
MTHFS, 80165368 rs2586154 A or G GG
MTHFS, 80168282 rs12899781 G or T TT
MTHFS, 80171971 rs16971478 A or G AA
MTHFS, 80172133 rs2586153 C or T CC
MTHFS, 80174388 rs2562744 A or C AC
MTHFS, 80177687 rs2733106 A or G AA
MTHFS, 80178283 rs12438477 A or C AC
MTHFS, 80182050 rs12898642 C or T CT
MTHFS, 80183766 rs2586182 A or C AA
MTHFS, 80184657 rs2733088 A or G AG
MTHFS, 80186340 rs12440798 C or T CC
SHMT1 18232096 rs1979277 A or G GG

Result from folinic acid - initial improvement with Health calcium folinate 800mcg - took less than 100mcg but had to stop after 5 days due to overmethylation symptoms.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Note that without knowing your reaction to folinic acid, your MTHFS and SHMT1 results are not really helpful. :)

Thanks!
I've been taking a b complex with 500 mcg of folinic acid for the last month or so. I really don't know the symptoms of folate deficiency for myself. I'm MTHFR +/+, but I made a recovery during a period where I was taking 1600 mcg of folic acid and no other folate:alien:

I disagree about people posting their SNPs without having tested folinic acid as not being helpful. While I agree that it's less helpful than if they had tried folinic acid, if we do find out which SNPs are responsible we'll have a better idea of what percentage of people here have that defect. If 23andme already has information on the percentage of people with that defect then I guess posting here without testing folinic acid would serve no purpose.
Thanks! If the person you mentioned with SHMT1 rs1979277 AG did testing with 23andMe it would be helpful if they could also post their MTHFS results.
I spoke to her last week. She was still fatigued after stopping folinic acid. She's been taking antibiotics so that could be what's causing it. My guess is she's not going to want to do any tests with folinic acid right now due to the state of her health. Hopefully when she's feeling better she's try again.:) When she posted her chart in another thread Caledonia told her to take folinic acid for SHMT. Does that mean that folinic acid normally would help someone process methylfolate, or is this some other function of SHMT that folinic acid is recommended for?
 

nandixon

Senior Member
Messages
1,092
When she posted her chart in another thread Caledonia told her to take folinic acid for SHMT. Does that mean that folinic acid normally would help someone process methylfolate, or is this some other function of SHMT that folinic acid is recommended for?

Rich and I talk about this in posts #4 and #5 of this thread.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Result from folinic acid - initial improvement with Health calcium folinate 800mcg - took less than 100mcg but had to stop after 5 days due to overmethylation symptoms.
I'm sorry to hear that. So you were taking 100 mcg once a day for 5 days? The reason why I'm asking is because you also mention 800 mcg in your post, but I guess you split it into eighths? And how much B12 were you taking (and what type of B12)?
 

brenda

Senior Member
Messages
2,266
Location
UK
I was taking 100mcg daily with small amount of anabol naturals Dibencoplex maybe 250 MCG.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
I was taking 100mcg daily with small amount of anabol naturals Dibencoplex maybe 250 MCG.

Oh ok. If it was helping you, maybe you could try just taking 100 mcg once a week. It's probably better than nothing and might not cause any problems since it took 5 days for you to experience symptoms. If that works ok you could eventually go up to twice a week. Have you looked into a CBS protocol? Someone said that could be one reason why a person would have a hard time tolerating methylation. I think Yasko even says to do that before methylation. And did you stop hydroxocobalamin because it was causing problems?
 

brenda

Senior Member
Messages
2,266
Location
UK
Good idea thanks. I did not get on well with yucca but have stopped eggs and eat little meat no. Not sure what else to do. I am back on hydroxb12 after going back on methylb12 so I'll see how that goes. Still working on my diet but good results so far.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Good idea thanks. I did not get on well with yucca but have stopped eggs and eat little meat no. Not sure what else to do. I am back on hydroxb12 after going back on methylb12 so I'll see how that goes. Still working on my diet but good results so far.

I don't know if working on CBS will help or not. I was just curious if you had tried. Rich said SNPs aren't always a good indicator of how a person responds to methylation so I'm not sure what to think now.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
In Lundell's 2006 paper (http://www.ncbi.nlm.nih.gov/pubmed/16889122), the narrowly defined subset of CFS/ ME patients in that study were able to tolerate a regime of 25mg of folinic acid 3-4 times per day, for a total of 75-100mg per day! I wasn't able to tolerate 1mg. Just offhand, I'd say that if you can't tell, for example, whether 4-8mg (= five to ten 800mcg tablets) per day makes your fatigue worse, then you probably don't have a significant intolerance to folinic acid.

I was wondering about that study and the dosages. Is there a limit in terms of how much folinic acid a person can convert into methylfolate? (assuming they can process it correctly) While some people might have a folinic acid intolerance like you, there are others who are sensitive to too much methylfolate so I was curious if that happens too. I tried taking 2000+ mcg of folinic acid a month or two ago and I think I felt sort of ill, but I'm not sure. I'm not as sensitive to methylation anymore so it's hard to tell the effects.
 

Bluebell

Senior Member
Messages
392
Hi, I'm trying to figure out if I should take a little folinic acid or not, along with a little methylfolate.

I have not tried either form of folate yet, as I'm just starting a methylation protocol and I have spent a week only taking what would be in a multivitamin/multimineral (which I am attempting to replicate with a lot of individual supplements because none of the pre-formulated multis seemed to be a good fit for me).

I have read this thread a couple of times and it seems that the thinking is:
-Taking folinic acid at the same time as methylfolate can be a help to people because it gives the body a form of folate that the body can use instantly for certain things that the body cannot use the methylfolate form of folate for, at least not instantly. Because of that, when overall methylation is poor, giving methylfolate only, at first, can starve the body of some of the benefits of folate in general. (When overall methylation is good, then this is not so much of a concern.)
-Most people, perhaps around 80% or more of people (even those who have some problematic methylation mutations, such as children with autism do), probably can tolerate and process folinic acid. Some people cannot though, and it makes them worse.
-Rich did well with folinic acid, Nandixon did not do well with folinic acid.
-The MTHFS set of genes determine whether or not a person does well with folinic acid.
-The SHMT1 snp also plays a role: a +/+ or +/- result might indicate that the person will not do well with folinic acid.
-If the people who do well and do not do well with folinic acid compare their MTHFS mutations and their SHMT1 mutation, maybe the resulting patterns can point to the most likely MTHFS snps that would indicate that a person would probably not do well with folinic acid and should take only methylfolate.

I have a couple of questions:
1. If the person has a "normal" -/- for SHMT1, then should the person be completely fine with taking folinic acid (no matter what the person's MTHFS mutations are)? Or does one have to look at both SHMT1 and MTHFS genes, in combination?
2. Are there any preliminary conclusions from this thread's MTHFS alleles chart about which SNPs might be involved in folinic acid tolerance?

Not that I am volunteering to reorganize the chart myself :) , but maybe the alleles of the people who have no problem with taking and processing folinic acid can be placed to the left of the rs number along with Rich's alleles, and the alleles of the people who did have trouble with folinic acid could be placed to the right of the rs number, because at the moment that important piece of the puzzle is not included in the chart.

====
Basis of thread

-Rich in post 4: "In order to use folinic acid a person must have a normally functioning MTHFS enzyme (not the same as MTHFR). If this enzyme is slow for genetic reasons, folinic acid can build up. and that will inhibit the SHMT reaction, which in turn will inhibit the normal production of MTHF, which in turn will hinder formation of DNA and formation of methylfolate."

-Nandixon in post 5: "if your MTHFS is not working well, i.e., not doing a good job converting folinic acid to methenyl THF (different than methylene THF) then you might be pretty sensitive to supplementing with folinic acid - because an excess will inhibit SHMT (folinic acid is both a product of SHMT and an inhibitor of that same enzyme).
Perhaps people are mostly only going to be sensitive to folinic acid when they have defects in both SHMT1 and MTHFS, but folinic acid also inhibits other enzymes, including the mitochondrial version of SHMT, which is encoded by the SHMT2 gene. (SHMT1, which Yasko tests for, is the cytoplasmic version.)
So if, for example, you're not sensitive to folinic acid, then perhaps your MTHFS SNPs will be more closely aligned with Rich's, or with mine if you are."
====

My results (below) are on the left side, Rich's are on the right.

Of the ones where mine are different from Rich's, my alleles appear to agree with most of the others' on the chart. If most of those folks do have trouble with folinic acid (though I'm not sure if they do), then maybe I would have trouble with it, too?

Because I haven't tried folinic acid yet, I didn't think adding my results to the main chart would provide any useable information to anyone, so I didn't go to the trouble to do that.

I am -/- for SHMT1, so I don't know if I shouldn't even worry about this. ??

mine...............Rich's
TT rs8923 CT
CC rs2733103 CC
AA rs16971427 AA
AA rs655473 AA
CT rs17284990 TT
AA rs16971450 AA
CC rs6495446 CT
AC rs7177659 CC
GG rs6495449 GG
AA rs17285431 AC
CT rs6495451 CT
GG rs2586154 GG
TT rs12899781 GT
AA rs16971478 AA
CC rs2586153 CC
NO CALL rs2562744 AA
AA rs2733106 AA
AC rs12438477 CC
CT rs12898642 CT
AA rs2586182 AA
AG rs2733088 AG
CT rs12440798 CC

AG rs685487
CC rs8033649

Because Nandixon said that SHMT2 also affects folinic acid processing, my SHMT2 results on 23andMe (although I don't know what they mean - does anyone know?) are:
GG rs12319666
AG rs34095989