Miles Nichols says, "Do you have any info on MTR and MTRR polymorphisms?
Are these clinically relevant?
Do they warrant methylcobalamin supplementation or injections?
Are there other considerations like glycine, choline and creatine that are important in
the cases of MTR and MTRR mutations?"
Okay, Miles, let me stop and give a little bit of background for everyone.
In the methylation cycle, I've talked a lot about MTHFR, which helps finalize the methyl
group of methyfolate.
But then folate has to donate that methyl group to vitamin B12 in order for vitamin
B12 to donate it to homocysteine.
In that process, that's how you clear homocysteine primarily in the fasting state rather than
the fed state.
It's also how you recycle homocysteine to methionine to use for methylation, again,
primarily in the fasting state rather than the fed state.
MTR is the gene for the methionine synthase enzyme, which is the enzyme that takes the
methyl group from folate, passes it to B12, and then passes it to homocysteine.
MTRR is a backup repair enzyme that repairs vitamin B12 once it's been oxidized.
MTRR is not a normal part of the methylation cycle.
It is a backup enzyme.
It's kind of like a janitor.
Only instead of coming in to mop the floors every day, it's like a cleanup crew that's
on call.
Most of the time, you're not using MTRR to even a tiny fraction of your maximal capacity
just because you don't have a lot of damage to the B12 molecule.
About once every 200 or 300 cycles of the methylation cycle, B12 will get damaged.
This is an average.
But once every 200 or 300 cycles on average, B12 gets damaged.
MTRR steps in and repairs it.
The reason that Miles is asking this is because I haven't really addressed them very much
in most of what I've written on methylation.
There's a reason for that, which is that—I'll address them in order.
Methionine synthase, there's a bunch of polymorphisms in it.
But the last time I did some research into this, I couldn't find very clear evidence
on mechanistically what those polymorphisms were doing to it.
If I don't know what the polymorphism mechanistically is doing to the enzyme, then it's hard to
build a nutritional program around it.
I came to the conclusion that the MTR is, you can say some maybe things about it.
I don't know if the polymorphism lowers the activity.
If it does, then what that means is that no matter how much methylfolate you have or how
much methyl B12 you have, you're not going to be very good at remethylating homocysteine.
So, it probably doesn't make any sense to inject methylcobalamin in that case.
It probably makes zero sense because you can’t use that enzyme.
Now, it's theoretically possible that the polymorphism causes a defect
in the methylfolate passing the methyl group to B12 and causes no defect in B12 passing
the methyl group to homocysteine.
In which case, maybe injecting methylcobalamin or oral methylcobalamin at high doses maybe
would do something there.
But I think that's an extraordinary level of speculation, and I think it's rather bizarre
to be injecting people with stuff on the basis of that level of speculation.
Now, my suspicion would be that if in fact the enzyme doesn't work very well, what you
actually would benefit from would be number one, doubling up on the choline just as you
would—actually, most of my MTHFR recommendations would make sense here.
Choline would make sense because if you can't use the folate-B12 pathway, you're going to
rely more on the choline pathway to remethylate homocysteine.
So, if in fact that enzyme does anything, it probably doubles the choline requirement
like the MTHFR polymorphisms do.
I was going to say it might make sense to you, Sammy, but I take that back.
I don't know if it would.
The other thing in the methylation protocol that would make sense there is creatine because
creatine would lower your methylation demand.
However, I don't think it would be as important to put creatine in there, because in this
case you don't have a problem making methylfolate if everything else is working fine, and theoretically
you should be fine at using choline for supporting methylation.
The reason that I have the creatine in the MTHFR protocol is because I'm trying to spare
methylfolate as much as possible because methylfolate is the off switch for the glycine buffer system.
I want to reduce methylation demand so that the system is not incentivized to use up the
methylfolate that you put into it.
Because when it does, you're not very good at regenerating the methylfolate, and the
low methylfolate levels will cause you to lose glycine.
That's why glycine is in the protocol.
If your MTHFR is working fine, then the creatine is much less relevant, and the glycine really
isn't that relevant.
Glycine is still important for everyone, but it's not specifically relevant because of
the genetic variations.
With that said, I do think that because some tissues rely more on folate and B12 than they
do on choline that there might be some tissues that would benefit from supplementing creatine,
so you could play around with it.
I supplement creatine, and I don't have any problems.
I mean, there's no harm in trying out the creatine.
Now, moving on to MTRR.
My MTRR looks like a nightmare.
I'm homozygous for one of the polymorphisms that reduces the activity three to fourfold,
and I am heterozygous for another polymorphism that also reduces the activity three to fourfold.
I don't know exactly what that adds up to, but my MTRR might be five to six to seven
times lower function than normal.
Does that matter?
Well, the way it would matter if it did matter would be that when I am exposed to oxidative
stress, my B12 would get damaged at a higher rate than normal.
And when it does get damaged, my MTRR would not be up to the task of fixing it.
The reason the MTRR polymorphisms that lower the activity three to fourfold are so common
is because either they're advantageous or they don't matter that much.
I believe the reason is that they don't matter that much.
They do matter when you are exposed to higher than average oxidative stress.
In my view, there's no blanket recommendation for someone with MTRR polymorphisms.
What I say is because in theory you will be bad at repairing B12 when your B12 gets very
damaged, you should thoroughly look at your B12 status at least once.
Then every time you enter a new health era, you should monitor your B12 status again.
What I mean by health era is your health changes or your developmental stage changes in a way
that could impact your health.
So, change in health eras, and I'm making this term up, this is not a medical term,
but the change in health eras means you get sick with a sickness you never had before.
That's a change in your health era.
Or you go through puberty.
That's a change in your health era.
You go through menopause.
That's a change in your health era.
Or you go on birth control.
That's a change in your health era.
Any time where you say, "I have good reason to think things might be different for me
now than they were before," measure your B12 status again.
When I say thoroughly look at your B12 status, I mean look at your serum B12, look at your
homocysteine, and look at your urine or blood, preferably both, methylmalonic acid, aka MMA,
not mixed martial arts.
Look, my MTRR, as I said before, looks terrible on paper.
But when I was at the peak of my mold and barium crisis, and when I went on an antifungal
drug that interferes with the methylation system in the fungus where there's a case
report of someone with, I think it's MTHFR, getting neurological problems from using it,
and I thought I was getting neurological problems from being on the antifungal, I measured everything
I could think of about my B12 status, and everything looked fine.
I'm not talking about just serum B12.
I'm talking about all the functional markers too.
They looked just fine.
That just reinforced my belief and the observational data that these things are so common.
If these things dramatically impacted your B12 status in a very negative way most of
the time, not many people would have the polymorphisms.
And yet, they're very common.
Those are huge reductions in activity.
They're very, very common.
So, I think it's ridiculous to make a generalized nutritional protocol around either of those.
MTR, it gives you a couple ideas you can experiment with.
MTRR, be proactive about monitoring your B12 status.
All right.
Thank you for your question, Miles.