homozygous for MTHFR A1298C - heterozygous for MTHFR C677T

[Prefect]

I apologize for my utter noviceness on this issue but I just got my 23andme result and was curious if I can get help understanding what this means:

MTHFR A1298C position 11854476 SNP: rs1801131 Genome: GG
MTHFR C677T position:11856378 SNP: rs1801133 Genome: AG

Can anyone explain what the implications are in laymen terms?

Thx

 

[Prefect]

I should add, these are both posted on the minus strand

 

[Valentijn]

MTHFR A1298C position 11854476 SNP: rs1801131 Genome: GG
MTHFR C677T position:11856378 SNP: rs1801133 Genome: AG

A1298C is fairly mild, unless combined with C677T on the opposite strand. Since you are homozygous for A1298C, that means you're definitely compound heterozygous. Hence enzyme activity is reduced to approximately 30% of normal.

Due to these mutations being extremely common, it's a pretty normal situation to be in. Research into those mutations has shown that a diet with a decent amount of vegetables, or supplementing a normal amount of folate, is sufficient to remove the increased risk factors of birth defects. So the same dietary or supplement intake is probably more than enough to compensate for any other problems that might arise from impaired methylation.

 

[Prefect]

I eat salad usually containing kale, arugula or spinach practically everyday, have for years. I also take a multivitamin that has folate which I read here is apparently a bad idea? Should I be looking for a methylfolate supplement?
What about the impact of A1298c on bh4 levels? I've had psychiatric problems for 20 years

 

[PeterPositive]

I eat salad usually containing kale, arugula or spinach practically everyday, have for years. I also take a multivitamin that has folate which I read here is apparently a bad idea? Should I be looking for a methylfolate supplement?

Probably not.
You could test your homocysteine levels and see if they are in range. If not, then supplements will help (methyl-folate and B12 in particular)

cheers

 

[Prefect]

But what I'm saying is I understand I should take methylfolate and B12 for C677T mutation, but should I be taking BH4 to correct for A1298c?

 

[alicec]

should I be taking BH4 to correct for A1298c?

The A1298C SNP has nothing to do with BH4.

This is one of Yasko's completely unfounded claims. The SNP has the same effect as the C677T SNP (though to a lesser extent). It simply slows the normal action of the enzyme which creates methylfolate from 5,10 methylene THF.

The MTHFR enzyme does not run backwards and methylfolate does not regenerate BH4. This claim is based on a misreading of a research paper in which conditions were manipulated in the test tube to make the enzyme run in reverse.

Some enzymes in the folate cycle do run in both directions but there is no evidence that MTHFR is one of them.

There is an indirect connection between methylfolate and BH4, in that methylfolate acts as a peroxynitrile scavenger and so has a BH4-sparing effect.

 

[caledonia]

If I'm reading your SNPs correctly that means:
A1298C +/+
C677T +/-

In that case, congratulations? - you're in a relatively rare category of having three MTHFR mutations. You're only the third or fourth person I've seen online with three mutations out of hundreds of people. The three mutations together would create about a 70% loss of function.

These mutations could help explain mental health issues, as methylation is required for neurotransmitters to be created.

The salad is probably ok, unless you're an "overmethylator" according to William Walsh. In that case, folate can actually cause depression instead of helping it. The work around is avoiding folate (even salads) and taking SAMe and maybe a few other things.

If the folate is folic acid, that could be problematic. The reason is you have a C766T mutation, so it's more difficult for you to convert the folic acid to methylfolate. In addition, any unmetabolized folic acid could cause cancer. You may also want to check the foods you eat for added folic acid (usually grains), and get those out of your diet.

The multi could be problematic. The reason is usually multis have less B12 than folate. That can cause methyl trapping over the long term. In addition, the B12 is oral, which means it only absorbs about 1-2%. The way around it is to take sublingual B12 or B12 injections, making sure to take more B12 than folate. The methyl B12 form is already converted so your body doesn't have to do the work. The artificial cyanocobalamin form is subject to the same absorption issues as folic acid.

There isn't really anything settled on what to do about A1298C that I have seen. If it's like what AliceC is saying, then general methylation support should be sufficient.

If you decide to stop your multi and try methyl B12 and methyfolate, it's best to start with very low doses like 50mcg or less, test one supplement at a time, then gradually work your way up to a normal dose as tolerated. I have info on how to do this in my signature link, what the pitfalls may be, and how to quickly stop side effects if you overdo it.

Check out "Start Low and Go Slow" and "Roadblocks to Successful Methylation Treatment".

It may or may not be necessary to do mega doses as some people do on here.

 

[Prefect]

So I need to go to the heath food store buy methyl B12, methylfolate, both ideally in liquid form or some form I can taper slowly? Any brands you recommend? I live in Canada.

Will drop my multivitamin but continue eating salad.

Oh and also, when it comes to trying sups for this theory, how long should I give it before I should expect to feel one way or the other?

 

[Valentijn]

There isn't really anything settled on what to do about A1298C that I have seen.

The function of the MTHFR gene is pretty well settled, and there isn't going to be a mutation which has completely different effects compared to other mutations on the same gene.

 

[caledonia]

So I need to go to the heath food store buy methyl B12, methylfolate, both ideally in liquid form or some form I can taper slowly? Any brands you recommend? I live in Canada.

Will drop my multivitamin but continue eating salad.

Oh and also, when it comes to trying sups for this theory, how long should I give it before I should expect to feel one way or the other?

I use Douglas Laboratories Methylcobalamin Liquid.

You may or may not be able to get them at the local health food store. I get all my stuff online.

https://www.amazon.com/Douglas-Labo...keywords=douglas+laboratories+methylcobalamin

I don't think there is a liquid for folate. In the past I've used Metagenics Folapro. Any brand which is actually methylfolate is ok - Solgar is another one. Maybe you can crush it into powder and use whatever sticks to the damp end of a toothpick for starters.

How long to notice a difference? It's hard to say. It could also depend on the dose you're taking.

You could feel something right away, either good or bad. You might feel good at first, then it fades away. You might start to feel worse several weeks later (as other deficiencies crop up).

It might take awhile for things to heal in your body if you've had long term deficiencies. So you might not feel much, but looking back, you might notice that certain symptoms have gone away.

 

[Prefect]

[

it's best to start with very low doses like 50mcg or less, test one supplement at a time, then gradually work your way up to a normal dose as tolerated

I just bought:

Pure Encapsulations B12 (Methylcobalamin)1000mcg in liquid.
Douglas Labaratories Methyl Folate (Metalfolin) 1000 mcg in tabs.

Is there a B12 to folate ratio I should begin with? I vaguely remember you discussing something about the ratio between the two being important.

And I guess I take both with meals?

Thanks for all the advice Caledonia.

 

[Prefect]

supplementing a normal amount of folate, is sufficient to remove the increased risk factors of birth defects

If not, then supplements will help (methyl-folate and B12 in particular)

If it turns out I don't have this condition is there any harm in taking methylfolate and methylcobalamin?

 

[caledonia]

[

I just bought:

Pure Encapsulations B12 (Methylcobalamin)1000mcg in liquid.
Douglas Labaratories Methyl Folate (Metalfolin) 1000 mcg in tabs.

Is there a B12 to folate ratio I should begin with? I vaguely remember you discussing something about the ratio between the two being important.

And I guess I take both with meals?

Thanks for all the advice Caledonia.

It's best to have somewhat more B12 than folate so you don't get into methyl trapping. I don't think there is any concrete rule of an exact ratio, but typical doses I've seen are 1000mcg B12 with 800mcg folate (as an ending dose, not a starting dose).

So that's 25% more B12 than folate. You can extrapolate from there with smaller doses. So take whatever dose of folate you want to start with, and add 25% of that to get your B12 dose.

So for example, 50mcg of folate x 25% = 12.5mcg. 50 + 12.5 = 62.5mcg of B12

I take mine with meals. I don't know if it makes any difference, that's just what's convenient for me and helps me remember to take it.

 

[caledonia]

If it turns out I don't have this condition is there any harm in taking methylfolate and methylcobalamin?

You could possibly get into an overmethylation situation. That's why you should have niacin on hand before you start, and start very low and work up gradually.

 

[Sea]

If the folate is folic acid, that could be problematic. The reason is you have a C766T mutation, so it's more difficult for you to convert the folic acid to methylfolate. In addition, any unmetabolized folic acid could cause cancer. You may also want to check the foods you eat for added folic acid (usually grains), and get those out of your diet.

Caleonia do you have a source for that information? I see that claim repeated everywhere that MTHFR information is available but I have never seen any evidence for it, though I have searched and questioned. When I have asked Dr Lynch and others I have been ignored or abused. It is true that some people do not process folic acid, but I have yet to find evidence that it is the C677T mutation responsible for that.

Logical evidence against a C677T mutation creating difficulty with processing folic acid is that the mutation raises the risk for neural tube defects and cleft palate in offspring and folic acid supplementation has seen the rates fall dramatically. If those with the mutation could not process folic acid there would be no fall in the rates of defects with supplementation.

It is far more likely that the problem with converting folic acid to usable folate occurs somewhere else in the folate cycle, probably somewhere that doesn't effect rates of neural tube defects.

 

[alicec]

It is true that some people do not process folic acid, but I have yet to find evidence that it is the C677T mutation responsible for that.

It is far more likely that the problem with converting folic acid to usable folate occurs somewhere else in the folate cycle,

It's hard to see how the C677T SNP could be involved in processing folic acid since the MTHFR enzyme is not responsible for metabolising folic acid.

That is done by dihydrofolate reductase (DHFR). It deals with folic acid in two steps, first converting it to dihydrofolate (DHF) then converting this to tetrahydrofolate. This second reaction is the normal reaction for this enzyme in the cell - ie DHF is the natural substrate for DHFR. Because of structural similarities, it is able to recognise synthetic folic acid and reduces it by the same mechanism as it uses for DHF.

It doesn't do it very well though so folic acid is processed slowly in everyone and in some people, very slowly indeed.

 

[caledonia]

Caleonia do you have a source for that information? I see that claim repeated everywhere that MTHFR information is available but I have never seen any evidence for it, though I have searched and questioned. When I have asked Dr Lynch and others I have been ignored or abused. It is true that some people do not process folic acid, but I have yet to find evidence that it is the C677T mutation responsible for that.

Logical evidence against a C677T mutation creating difficulty with processing folic acid is that the mutation raises the risk for neural tube defects and cleft palate in offspring and folic acid supplementation has seen the rates fall dramatically. If those with the mutation could not process folic acid there would be no fall in the rates of defects with supplementation.

It is far more likely that the problem with converting folic acid to usable folate occurs somewhere else in the folate cycle, probably somewhere that doesn't effect rates of neural tube defects.

It's not all or nothing. If you had one C677T mutation, for example, you would still have a 70% capacity to process the folic acid.

This looks like a pretty good summary of your question:
https://www.mthfrsupport.com.au/folic-acid-vs-5-mthf-treating-mthfr-deficiency/

As far as what AliceC is saying, of course, the folate pathway is not so simple as one step between intake of folic acid and then going to MTHFR. There are many steps in the process.

 

[Prefect]

It's not all or nothing. If you had one C677T mutation, for example, you would still have a 70% capacity to process the folic acid

One thing I'm curious about though about all this is, if my my body isn't converting folate into forms required for various body functions, shouldn't I have anemia?

 

[alicec]

It's not all or nothing. If you had one C677T mutation, for example, you would still have a 70% capacity to process the folic acid.

Please tell us how this is possible? What is the source of this claim?

This looks like a pretty good summary of your question:

The article doesn't answer the question at all. It says what I said in the earlier post. Folic acid is processed by DHFR not by MTHFR.

The article points out that accumulating folic acid can adversely affect aspects of the folate cycle (including the MTHFR reaction) though it doesn't really explain the mechanism (apart from referencing an in vitro study showing competition with natural folates for uptake into cells).

The main mechanism is that accumulating folic acid inhibits DHFR which means that DHF accumulates and this in turn has an inhibitory effect on several other folate enzymes. This is typical feedback inhibition used to tightly regulate interdependant metabolic pathways.

The article then goes on to describe some of the general consequences of accumulating folic acid (eg on immune system, cancer) and studies comparing supplementing with folic acid and methylfolate.

Nothing about the C677T SNP affecting folic acid processing (which of course is a physical impossibility).