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Help please? Homozygous for MTHFR C677T / COMT V158M / COMT H62H / VDR Bsm

Messages
30
I have been very ill for 4 years, firstly diagnosed with CFS/ME and then in 2015 I tested positive for Lyme Disease.
I believe I have a vitamin B12 Deficiency (yet my tests constantly come back sky high) and that I have a blocked methylation pathway.

My 23andMe results indicate I need help in this area (Genetic Genie Interpretation attached).

I am homozygous for MTHFR C677T /
COMT V158M / COMT H62H / VDR Bsm

I am heterozygous for MAO-A R297R/ MTR A2756G/ MTRR A66G / CBS C699T.

My Mother almost died 20 years ago when they failed to diagnose Pernicious Anaemia, after 9 months deteriation she collapsed and it took 17 days in hospital before they found it. My Father died of Parkinsons. I am now bedridden most days and I'm convinced there is a link here.

I do know that with my combination of MTHFR and COMT I need to be very careful with what I take. I'm highly sensitive to most things.

I would appreciate any advise. Too ill to work this out on my own. Does anyone know of a specialist who I can consult with via Skype or phone? (I am in the UK ).
ANY help at all with this, I'd be most grateful !!
 

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Messages
1
Following - I have the same mutations as you except I'm -/- for the CBS C699T, but I am hetero for CBS A360A.
I am new to all this so I can't comment, sorry.
 

alicec

Senior Member
Messages
1,572
Location
Australia
I believe I have a vitamin B12 Deficiency (yet my tests constantly come back sky high)

High levels in blood could indicate that the vitamin is not being used - ie it is accumulating in blood rather than being taken up into cells.

In my own case, I had never supplemented B12 apart from the small doses of cyanocobalamin in a multivitamin, yet blood tests for B12 were very high. The doctors who ordered the test had no comment. When I asked what high levels might mean they had no clue.

Later I had an organic acids test (OAT), which showed that the methylmalonic acid (MMA) marker was very high. This indicates that a functional B12 deficiency is present (the enzyme processing MMA is B12 dependant. It accumulates when this enzyme is not working properly).

As I began reading more I began to appreciate that the high serum B12 was a clue that I had not previously understood.

Supplementation with methyl and adenosylB12 soon returned the MMA to normal levels.

So apart from revealing frank deficiency, blood tests for B12 are not particularly helpful. A better test for B12 status would be either a blood test for MMA, or an OAT, which measures many metabolic products in urine, including MMA. It can be helpful for revealing a variety of functional metabolic defects.

I might add that for me, an analogous situation applied to folate. I had only ever supplemented the small amounts of folic acid in a multivitamin, yet had very high blood levels. The OAT also showed a functional folate deficiency which was remedied by methylfolate.

Regarding your SNPs, the homozygous MTHFR C677T would cause a marked slowing of the enzyme. Supplementation with methylfolate could be helpful, along with the cofactor (B2), which may help stimulate the enzyme.

The +/+ COMT V158M would also slow the enzyme, so supplementation of its cofactor magnesium may be helpful.

It is a myth that COMT+/+ means intolerance of methyl groups. Some people are certainly sensitive, but it is nothing to do with COMT.

Since you say you are sensitive to many things you would be very wise to approach methylfolate and both B12s very cautiously. Start very low and build up very slowly.

The +/- SNPs for MTR A2756G/ MTRR A66G would also slow the enzymes and hence use of B12.

The other SNPs don't amount to much.

There is much discussion of B12/folate protocols on PR. There are different versions and different responses. Many people have benefitted but many have found them problematic. These active vitamins can have powerful effects.

Given your's and your parent's history, B12 could be profoundly important for you so it is worth trying. Just proceed very cautiously.
 
Messages
30
Alicec, I am so grateful for your response. I'm so ill and no treatment I seem to trial helps. I recently returned from 3 weeks in hospital in Germany hooked up to IV 4 times a day. Still no improvement and often too sick and ill to get out of bed. Thank you for your very welcome advice you have shared here. When I first got ill 4 years ago I was convinced it had something to do with Vitamin B 12 deficiency. But like you every doctor just shrugged and had no help with why my blood tested so high for Vit B 12. They certainly wouldn't entertain that perhaps it indicated my body wasn't actually utilising the B 12 (here in the UK they are very limited in thinking outside of the box). I believe I must give this a try. May I ask you, can you please advise exactly how you would start this if you were me? I'm too poorly to research it in depth. I will start low and slow. But what do I take ? I have not taken any vitamin or mineral supplements (except magnesium which I take daily) for 2 years now. If you feel you'd rather not offer me more advice, do you know of any expert that would be willing to assist me that I could make an appointment with via Skype (there are pretty much no experts practitioners available in the UK who understand the SNPs or the B 12 issues I have). Thank you with gratitude again.
 

alicec

Senior Member
Messages
1,572
Location
Australia
They certainly wouldn't entertain that perhaps it indicated my body wasn't actually utilising the B 12

Here is a recent review of the high B12 phenomenon. B12 deficiency, as revealed by elevated MMA and homocysteine, is a common reason for it.

May I ask you, can you please advise exactly how you would start this if you were me?

A few general considerations first.

Metabolic derangement seems to be characteristic of CFS/ME and OAT tests which people have shared on PR show a variety of metabolic blockages/slow points.

Adding active B12s and folate can have widespread metabolic consequences, stimulating various pathways that have maybe not been functioning well. Sometimes this can be unpleasant.

Other nutrients involved in these pathways may become limiting, causing an initial positive response to peter out, or maybe never start at all. It may be necessary to supply various nutrients as well as the B12s for optimal effect.

Different protocols have been proposed for how best to get these active vitamins to work.

One which has been discussed a lot is Freddd's active B12 protocol, aka the deadlock quartet (or DQ; it contains 4 elements {both B12s, methylfolate and carnitine} each of which can deadlock the effectiveness of the others if it becomes limiting).

Here is a thread discussing it (there are plenty of others). Some PR members have written their own guides to this - eg here.

Another approach, the Simplified Methylation Protocol, proposed by Rich Van Konynenburg, differed in suggesting hydroxyB12 might be more suitable for people with adverse reactions to the active B12s.

There was much discussion back and forth but it appears that Rich's protocol is not much used these days.

Some people do seem to benefit from injections of very large doses of hydroxyB12 (where the large doses do other things like scavenge NO), but Rich's protocol uses small amounts and I think in principal is different.

Personally I don't advocate Rich's approach. I think the suggestion the hydroxy doesn't cause the same problems as the active B12s is because it is doing very little. But some people did benefit from the approach I believe.

Anyhow, recently a thread started trying to compare Rich's approach with yet another version advocated by the scientist who runs B12 oils (transdermal B12 products). There weren't many advocates of Rich's approach but interesting things were revealed about the ideas of Greg from B12 oils.

Essentially he differs from Freddd in saying that it is B12 plus B2 that is needed. When sufficient active B2 is available the often large amounts of folate needed in Freddd's protocol, as well as carnitine, are unnecessary - we can make our own.

(The enzyme which recycles folate is B2 dependant, and carnitine synthesis also requires B2).

The catch is that for some people at least, making active B2 from riboflavin has multiple stumbling blocks (eg good thyroid function, a good supply of minerals such as molybdenum, manganese, selenium as well as iodine). This might be the biggest hurdle of all in using active B12s.

My own experience suggests that much of what Greg says is correct and his transdermal B12 products are great, but too potent a place to start for sensitive people.

In the beginning I don't think you should count on being able to make your own methylfolate so some of that will be necessary in addition to B12 to get things going.

If later you find yourself needing large amounts of folate then I think Greg's analysis applies - you are not making enough active B2 to recycle folate properly. You would need to concentrate on that (various ideas discussed in the thread I linked).

I suggest you start with the sublingual approach suggested by Freddd. The basic idea is to start with a small amount to gauge response. You want an amount that you maybe notice but that is not too unpleasant. Reduce the starting amount if necessary.

Then you want to titrate up (slowly) - ie add more until an increase makes no difference. If you are tolerating and positively responding to larger doses of the B12s, then you could consider changing to the B12 oil products (much better than a mouthful of sublinguals).

The basics supplies to start with would be: -
MethylB12 - Enzymatic Therapy B12 Infusion, sublingual 1 mg
Methylfolate - Solgar Metafolin (called folate on bottle), 400 microgram tablet
AdenosylB12 - Source Naturals Dibencozide, sublingual 10 mg.

There are other brands but these are known to be potent and a good place to start. There is quite a bit of variability in potency, especially in B12s.

You probably want to have on hand a potassium source - either potassium gluconate powder or potassium chloride capsules - and niacinamide.

This is because need for potassium can increase suddenly and cause unpleasant symptoms. Greg says this shouldn't happen if B2 is working, but maybe it isn't and a bit of potassium can be a great help. If needs become very great then B2 becomes the issue to address.

Niacinamide can have a "quenching" effect if you get overstimulated from too high a dose.

Where you start depends on how sensitive you think you are likely to be - but maybe 1/2 or 1/4 of the MeB12 and methylfolate to start with.

Swallow the folate and place the B12 lozenge between upper lip and gum (dissolves more slowly than under the tongue, giving better absorption). If this is ok, repeat a few hours later. If too powerful, wait a day or two and try 1/2 that dose. You might aim for 3 or 4 doses in a day.

How quickly you increase dose depends on your response and how brave you feel.

As the guides and the threads indicate you may get unpleasant symptoms which could indicate a need for potassium and/or folate. Sometimes it can be hard to tell which is needed. You need to experiment by adding more and seeing what symptoms respond to what. Take folate away from potassium.

Once you are tolerating 1 or 2 mg MeB12, you might try adding in adoB12. Start with just a tiny sliver of the 10 mg lozenge.

Given you are not supplementing anything other than magnesium, you need to consider the issue that other things might become limiting very quickly. Freddd lists a lot of basics but these can be daunting to someone who is not supplementing at all. You will need to make you own decisions about all that depending on your own problems and responses.

The B2 issue is critical but other B vitamins will also be important and this is probably the first thing you should think of adding. A low dose B complex could be helpful - without folic acid and cyanocobalamin. I saw a thread recently canvassing good ones - you could search for that. I would seriously consider additional riboflavin (very inexpensive) and also Source Naturals sublingual Flavin Mononucletide (the first step in B2 activation). You would probably need to cut this up, it is very potent, but it can be a good way of bypassing some of the blockages in making active B2. Start with the riboflavin to gauge response, try the FMN later.

Trace minerals could be very important. This is something you could think about a little down the track along with the other basics.

The carnitine issue is something you can also address down the line when you have other things in place. The only way to know if supplemental carnitine is a help is to try it but be warned, it can have a powerful effect. If it does help, then according to Greg's logic, this means you still don't have B2 right. But that is for later.

The main thing it to be alert to your own body's response and not worry too much about someone else's rules.
 
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Messages
30
Alicec, thank you so so much for taking the time to put all this most helpful information down. I'm very grateful indeed. I'm going to read through it all carefully and consider my next step. Thank you again.
 
Messages
2
Location
Durham England
Alicec, I am so grateful for your response. I'm so ill and no treatment I seem to trial helps. I recently returned from 3 weeks in hospital in Germany hooked up to IV 4 times a day. Still no improvement and often too sick and ill to get out of bed. Thank you for your very welcome advice you have shared here. When I first got ill 4 years ago I was convinced it had something to do with Vitamin B 12 deficiency. But like you every doctor just shrugged and had no help with why my blood tested so high for Vit B 12. They certainly wouldn't entertain that perhaps it indicated my body wasn't actually utilising the B 12 (here in the UK they are very limited in thinking outside of the box). I believe I must give this a try. May I ask you, can you please advise exactly how you would start this if you were me? I'm too poorly to research it in depth. I will start low and slow. But what do I take ? I have not taken any vitamin or mineral supplements (except magnesium which I take daily) for 2 years now. If you feel you'd rather not offer me more advice, do you know of any expert that would be willing to assist me that I could make an appointment with via Skype (there are pretty much no experts practitioners available in the UK who understand the SNPs or the B 12 issues I have). Thank you with gratitude again.



I am homozygous mthfr c777t and in the uk , chronically ill and just as frustrated!
I been ill with me for 6 years .
2 years ago I found out I was homozygous. I tried then but I’m giving it another go .
I’ve gone gluten free .
1000mcg of b12 for for days then increasing so far haven’t been able to tolerate folate
 

dannybex

Senior Member
Messages
3,561
Location
Seattle
It is a myth that COMT+/+ means intolerance of methyl groups. Some people are certainly sensitive, but it is nothing to do with COMT.

Since you say you are sensitive to many things you would be very wise to approach methylfolate and both B12s very cautiously. Start very low and build up very slowly.

The +/- SNPs for MTR A2756G/ MTRR A66G would also slow the enzymes and hence use of B12.

The other SNPs don't amount to much.

There is much discussion of B12/folate protocols on PR. There are different versions and different responses. Many people have benefitted but many have found them problematic. These active vitamins can have powerful effects.

Given your's and your parent's history, B12 could be profoundly important for you so it is worth trying. Just proceed very cautiously.

Wow. @alicec, I wish I had even 1/100th of the brain power you do.

I'm one of those SUPER-sensitive types. At least since 2011. There's a thread from then around here someplace where I thought I would literally crawl out of my skin after a doc I was seeing at the time overprescribed about six different methylation supps AT ONCE. It's spooked me ever since.

Anyway, thanks for the COMT info, that's one less thing to worry/obsess over.

My current situation seems very dire, but I'm hanging in there or I wouldn't be typing this. Here's what I think happened.

I've been wasting away for a decade, but in the past 6-6 years or so started putting on weight...but in the wrong place, around my middle. Ended up with worsening fatty liver/pre-diabetes issues. Hba1C and triglycericides have improved over the last year, but that's it.

In desperation I posted pics of myself in a private group on Facebook back in 2016. After over 400 replies -- going off in various tangents, a doc replied, telling me he thought I was in metabolic acidosis, and needed, among other things, glutamine and especially niacin to stop the breakdown of kyrnurenic (sp) and quinolinic acid levels. He said tryptophan was being broken down to make niacin, hence niacin would help stop that and also improve the dyslipidemia. The latter it did.

BUT...even after consulting with him twice since January, nothing else was getting better, in fact...things just got worse. My gut is a mess, digestion is TERRIBLE, and so I stopped the glutamine (which may have been RAISING ammonia levels instead of lowering them as he suggested) and also stopped the niacin, because even though it helps my circulation a little, I have a feeling it's been DEPLETING MY METHYL GROUPS BIG TIME. Plus, I just read that although it does lower some lipids, it can increase homocysteine because of that very reason. Does that make sense to you?

So coming back to B12, the only time I was able to tolerate it without any problems, was when I was prescribed shots waaaaay back in 2003, along with nebulized glutathione. I went from Mr. Wired But Tired, to...aaahhhhh, I think I'll actually make it. And I did, I went into about a 75% remission for six months.

Then I started getting more and more agitated (had stopped the glutathione at month 2), so in July of 2003, my doc at the time prescribed injectible thiamine. That was even more dramatic. I was so calm I thought I could quit the klonopin cold turkey. I didn't of course, although I cut way back, and again went into remission for the next 2 years.

Of course, thanks to brain fog, I totally forgot about this later, but am wondering what you think about the notion of glutathione possibly helping to tolerate B12 better? I recall that was a hypothesis of Rich's.

I seem to tolerate the AD-B12 okay, or at least better than the MB-12. I last tried it about a month ago -- had a "better" day -- took 1mg nuggets held in my mouth about 3 times that day -- but then ended up not being able to sleep, and woke with strong muscle cramps. Does that sound like potassium deficiency? It could also be ammonia issues too...but it's just so overwhelming to figure out.

And weird question, but if the MB-12 seems to work...then would it help waking up to take it...or is this a question that probably is impossible to answer? I do have the oils, but after a 'better' day with the sublingual AD-B12s, I took about a half spray of them and again...was incredibly tensed up for a day and a half.

(I do take b2 -- have for years for eye issues -- but not sure what my mineral levels are.)

Now of course I've been that way almost ever since, but maybe a little better later in the day. Mornings are terrible, but after my second or third meal, I'm "better". I know I'm not getting nearly enough calories as it is, but even less so thanks to the severe digestive issues.

Despite all this, I'm certain I need the MB12. I have the book "Could it Be B12?" and just have SO many of the deficiency symptoms. One case study she mentions who was diagnosed with MS and then almost ALS who then recovered after MB-12 shots -- she mentions that he scored a 13 on a deficiency test she has in the back of her book. I got a 37 on that same test.

I'd appreciate your feedback. Thanks in advance.
 
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dannybex

Senior Member
Messages
3,561
Location
Seattle
@alicec Lastly, is it true that hydroxocobalamin can convert to either methylcobalamin or adenosylcobalamin?

I've seen this on many sites, but could only find one en vitro study in rat liver slices:

https://www.sciencedirect.com/science/article/abs/pii/0003986178902321

I think I tolerate it better than methyl-b12, but I did take 1/2 capsule yesterday, and today is worse, overstimulation-wise. I read that it has a much longer half life than the other forms.
 

alicec

Senior Member
Messages
1,572
Location
Australia
@alicec Lastly, is it true that hydroxocobalamin can convert to either methylcobalamin or adenosylcobalamin?

I've seen this on many sites, but could only find one en vitro study in rat liver slices:

https://www.sciencedirect.com/science/article/abs/pii/0003986178902321

I think I tolerate it better than methyl-b12, but I did take 1/2 capsule yesterday, and today is worse, overstimulation-wise. I read that it has a much longer half life than the other forms.

All forms of cobalamin are processed within the cell in the same way. First the upper axial ligand (the methyl, adenosyl, hydroxy or cyano group) is removed. The underivatised cobalamin is then directed to the two B12 dependent enzymes according to the needs of the cell. A methyl or adenosyl group is added at the relevant enzyme.

Theoretically it shouldn't matter what form is taken since they all end up the same. In practice many people report different response to different forms. The basis of this is not really understood and has not really been studied but it may have something to do with individual differences in uptake and/or processing of the different forms.

You should take the form that you tolerate best.