Compound Heterozygous C677T & A1298C

[acrosstheveil]

How would you go about treating these mutations? How much methylfolate woudl some require compared to someone who is homozygous c677t?

 

[Valentijn]

How would you go about treating these mutations? How much methylfolate woudl some require compared to someone who is homozygous c677t?

First of all, being heterozygous for both is only worse than being heterozygous for C677T if each bad allele comes from a different parent. If both alleles are from the same parent (on the same strand), then MTHFR activity is at 65% of normal. If each allele is from a different parent, then MTHFR activity is 30% of normal.

I don't think a dose over 400-800mcg is typically advocated, unless there's additional evidence of a problem with actual methylfolate levels. If interested in going higher, you really need to talk to a doctor about that.

The important thing is that you can't use folic acid very effectively. So any supplementing should be done with methylfolate. Alternatively, eating a diet with lots of veggies has the same compensatory effect as supplementing.

 

[shah78]

First of all, being heterozygous for both is only worse than being heterozygous for C677T if each bad allele comes from a different parent. If both alleles are from the same parent (on the same strand), then MTHFR activity is at 65% of normal. If each allele is from a different parent, then MTHFR activity is 30% of normal.

I don't think a dose over 400-800mcg is typically advocated, unless there's additional evidence of a problem with actual methylfolate levels. If interested in going higher, you really need to talk to a doctor about that.

The important thing is that you can't use folic acid very effectively. So any supplementing should be done with methylfolate. Alternatively, eating a diet with lots of veggies has the same compensatory effect as supplementing.[/q......................................................................................................................................................... Can you explain the "different vs same" parent source a littler further. also the 30% of normal function seems to be the same as a ++C677T situation.? I assumed compound +/- had better function than that. Do you have any cites for this ?. ( Note:always enjoy your answers)

 

[Valentijn]

Can you explain the "different vs same" parent source a littler further. also the 30% of normal function seems to be the same as a ++C677T situation.? I assumed compound +/- had better function than that. Do you have any cites for this ?

From what I recall, if both mutations are on the same strand (from the same parent) the other strand can do all of the work and keep things going at a normal level. Whereas if both strands have a mutation, the reduction in functionality is going to have an impact.

I can't do much citing at the moment. I've got a catheter sticking out of my hand so much typing is difficult, and getting a fever and such from the IV antibiotics. Not really up for going hunting! But I am quite sure that the studies I read showed that the compound heterozygous was as bad as being homozygous for C677T.

The only sources I have saved currently are http://digitalcommons.unl.edu/lawfacpub/124 for C677T (A222V) and http://www.snpedia.com/index.php/Rs1801131 has a good summary of and links to the sources for A1298C (E429A).

 

[shah78]

From what I recall, if both mutations are on the same strand (from the same parent) the other strand can do all of the work and keep things going at a normal level. Whereas if both strands have a mutation, the reduction in functionality is going to have an impact.

I can't do much citing at the moment. I've got a catheter sticking out of my hand so much typing is difficult, and getting a fever and such from the IV antibiotics. Not really up for going hunting! But I am quite sure that the studies I read showed that the compound heterozygous was as bad as being homozygous for C677T.

The only sources I have saved currently are http://digitalcommons.unl.edu/lawfacpub/124 for C677T (A222V) and http://www.snpedia.com/index.php/Rs1801131 has a good summary of and links to the sources for A1298C (E429A).

Amazing answer! thanks. The visualization of you typing with a catheter sticking out of your hand and answering some anonymous "schmuck" four thousand miles away is breathtaking. Only on a CFS/ME website! Goodluck

 

[sueami]

This from Ben Lynch:

Heterozygous = 1 copy of the gene from either parent
Homozygous = 1 copy of the gene from each parent (most commonly – some exceptions)

MTHFR C677T Heterozygous = 40% loss of function
MTHFR C677T Homozygous = 70% loss of function

MTHFR A1298C Heterozygous = No loss of function (debatable)
MTHFR A1298C Homozygous = No loss of function (debatable)

MTHFR C677T & MTHFR A1298C Compound Heterozygous = 50% loss of function

and he cites this study for these numbers:
http://jmg.highwire.org/content/41/6/454.full.pdf

I pulled the numbers from this page:
http://www.seekinghealth.com/media/MTHFR-Introduction-Basic.pdf

 

[sueami]

As far as how much mfolate, I was trying to push high doses and was up to 4mg when I found a methylation-aware physician and saw him. I was not doing well -- anxiety, flu-like feelings, worsened fatigue.

He wanted me to drop back to 400mcg based on my compound hetero status and go no higher than 1600mcg if I really felt I needed to push it higher. I seem to be doing best at about 800mcg, and I am taking 1 mg subdermal mb12 shots every other day (with 5mg sublingual tabs on the off days, plus 3-5 mg sublingual Adenosylcobalamin every day (estimating at best 25 percent absorption of the sublinguals.)

 

[sueami]

With your MTRR and MTR snps, you will need more MB12 and shots might work well with you. Unfortunately, you got CBS involvement -- that's going to suck up a lot of the folate/b12 you take down the sulfur detox pathway. Yasko believes CBS upregulations must be addressed first or you risk just diverting all your folate/b12 into that sulfur pathway that creates yucky metabolites as it works.

And you've got COMT and MAO A, like I do, so anxiety levels and mood instability are probably in play. I'm doing better going slower on the methylation, though the MB12 shots were a huge boost to energy, clarity and to a lesser extent mood. I'm looking to go on a very strict diet next to deal with the anxiety fluctuations I still have.

 

[shah78]

Thanks.

 

[ahmo]

@sueami Wow, what a great piece from Ben Lynch! Thanks so much for this link.

 

[acrosstheveil]

one of my issues lately is high histamine and i believe mast cell degranulation. I have tried increasing methylation with higher doses of methylfolate and tmg but I always end up with symptoms of overmethylation when I start clearing the histamine. It's like I either have high histamine or I am overmethylating. It has been impossible for me to find a balance. I have just recently begun all sorts of anthistamines and mast cell stabilizers with some but little improvement.

i think i may need to increase my b12 supplementation, but the question is, by how much? And do I need to be taking hydroxcobalamin as well as methylcobalamin?

some of my symptoms are very low energy, extreme tinnitus, insomnia, bloating, visual disturbances, chest pain, shortness of breath, vasoconstriction, and irritability.

do I need to be supplementing with 5-htp to increase serotonin levels?

 

[ahmo]

@acrosstheveil Sounds like you need more MB12. I wouldn't take hydroxy, tho I know Yasko suggests it. I'm also MAO++, have mast cell issues. I found that on the occasions when increasing my MFolate dose gave me histamine symptoms, I could take a 1mg MB12 and stop the symptoms almost immediately. Alternatively, Ben Lynch recommends using B3/niacin to dampen the effects, effectively slowing methylation.

Re how much Mfolate/B12, no precise answer. You might get some insight in the compilation of Freddd's comments linked in my signature. Once I'd gotten into a reasonable dosage, my life-long insomnia stopped. gone.

Re anti-histamines, do you know of rutin, mangosteen, quercetin, royal jelly? I've had amazing results w/ rutin, again, stopping histamine reactions almost immediately. I switched from quercetin, which is moderately high thiol/sulfur once I discovered mangosteen. And royal jelly is oriented toward mast cells.

I'd used 5 HTP for some years, and then it became excitotoxic for me. Be cautious.

I found my tinnitus and irritability disappeared when my adrenals cleared after an long period of detox. My tinnitus has become a barometer, coming and going as a hiss when adrenals are stressed. Are you doing any detox? Eating gluten or gluten cross-reactive foods?
http://blog.primohealthcoach.com/blog/bid/79586/18-Gluten-Cross-Reactive-Foods

 

[acrosstheveil]

yes, i've been taking ascorbic acid and quercetin for qhite some time. I do not eat gluten and avoid it at all costs. I"m going to try raising my methylfolate dosage and ordered some adenosylcobalamin. I ran out several months ago and never restocked. maybe thats why im so tired.

 

[musicchick581]

@sueami ...our snps are almost identical I think...wow

 

[lilly23]

@Suami. Thank you for posting this. I've been googling till the cows come home. I am also compound hetero. I know there are other things involved but what have you found to be the best folate to B12 ratio? Are you unable to take methylfolate?

This from Ben Lynch:


He wanted me to drop back to 400mcg based on my compound hetero status and go no higher than 1600mcg if I really felt I needed to push it higher. I seem to be doing best at about 800mcg, and I am taking 1 mg subdermal mb12 shots every other day (with 5mg sublingual tabs on the off days, plus 3-5 mg sublingual Adenosylcobalamin every day (estimating at best 25 percent absorption of the sublinguals.)

 

[sueami]

No, I'm back up to about 3.2 mg folate right now (2 800mcg tabs, twice a day. Sometimes I'll take one more at dinner time.) I've also doubled my mb12 shots to 1 mg daily. Then I also take 6 or so 1mg tabs of mb12 on the assumption that I'm absorbing about 1.5 mg from those (I figure on a 25 percent absorption rate). I also take 8.6mg adb12 daily (which I hope translates to 2 or so mg absorbed).

I'm shooting for a 1 to 1 ratio, mostly because I have no hope of making the 2-1 mb12 to mfolate ratio that Freddd says is best for him. He has access to 10 mg injections that help him get high absorption of mb12. He might also need wildly different amounts of MB12 and mfolate than the rest of us do. He certain was far sicker that I was and for far longer.

My best guess for why I had trouble early on is that some of my snps were messing with my neurotransmitter levels (MAO A and COMT) and methylation startup was increasing that instability. I think starting low and going slow is excellent advice for those of us with those snps, even if we don't feel particularly sensitive to supplements, which I did not think I was when I started.

I was able to raise my levels after a couple months and I'm in a pretty nice upward climb right now, with of course the occasional enormous speed bump because life would be boring if things went well all the time.

I've been as low as 2.5 or 3 activity level this year and right now I'm somewhere between 5 and 6.

I keep meaning to post a thread on this but haven't had time. I have gotten some really interesting feedback from the researcher behind the b12oils.com site. He's a phd who's been researching b12 for 25 years, he says, and this is the analysis he gave of my snps. Since at least one other person on this thread (@musicchick581 ) has similar snps, I'll paste it in. I find it useful to read this sort of thing even if the genetics are a bit different than mine.

I have not yet trialed the folinic acid he recommends, but I plan to, finances permitting. I am starting on his MB12 transdermal oil and will report back on it's efficacy, as best I can determine it, in a couple weeks.


Looking at how people go with the profiles, I think that the major problems/concerns are really the +/+ mutations. Generally if you have +/- it means that one copy of the protein is working properly. 50% of the population will have +/- so one has to assume that one does reasonably well on it.

Mutations in any of the cycles are cumulative, so that if you have say 2 genes with mutations in the folate cycle, the cycle will run very slowly. It is like a series of large pipes, with one very small pipe in the series. The flow of water depends upon the smallest pipe. Thus if you have +/+ this restricts you flow dramatically. Now the other thing is that all the reactions "back up" behind the restriction.

In the data that I have sent you back you will see a column that has the co-factors (the enzyme helpers) that are required for the enzyme to work properly. With nearly all the mutations, the mutations mean that the enzyme can lose hold of the co-factor if the concentration drops. Thus, if an enzyme needs FAD (from vitamin B2) and there is a mutation in the enzyme, it is critical that you keep the levels of the vitamins very high. You will see that basically you need SAM, FAD and pyridoxal phosphate as the main co-factors.

Going through your mutations (+/+) you can see major problems in your folate cycle with Methylenetetrahydrofolate dehydrogenase, 5,10 methylenetetrahydrofolate synthase, and serine hydroxymethyltransferase. FYI you are the only person that I have seen with this series of mutations as +/+. Your folate cycle will run very slowly. You will also have trouble with utilizing folate (folic acid) as once you have made THF, SHMT is the enzyme for taking it into the folate cycle. I would think that for your folate supplementation you will need to incorporate folinic acid. Your MTHFR alleles means that you will need to also have 5MTHF to run your methylation cycle (obviously you know this. 5MTHF is the normal dietary folate).

Looking at the generation of SAM, which can come via Betaine, 5MTHF/MeCbl/MTR, or methionine, your BHMT +/+ means that supplementing with betaine is probably not going to be great. Now it appears that we evolved to get methyl groups from betaine and up to 50% of SAM is normally generated from betaine.

You have MTRR +/+, which means that your usage of methylB12 is very high, as you can't convert oxidized Co(II)B12 back to Co(III)B12, so you will be continually having to supplement in with more MeCbl. The other problem is that you wil basically not be able to supplement with CN-B12, because you use MTRR and decyanase to kick the CN group out of CN-B12. Studies also suggest that hydroxyB12 will not be very useful for you.

Now, there is another associated methylation problem with your PEMT mutation. PEMT is normally involved in using SAM to convert phosphatidylethanolamine to phosphatidylcholine. Now this could be seen as an advantage as you can't use SAM and you would think that this would put less strain on your SAM, BUT you need to make phosphatidylcholine (PC) for you lipids in your cell membranes. An alternative pathway is to make PC from choline. In this case however, you will sacrifice your choline, which is used in making acetylcholine, which is one of your most important neurotransmitters. To overcome this, you will need to have lecithin which is basically phosphatidylcholine. It comes from eating eggs.

The other major snp you have is in MAO. This is the most common double mutation seen in CFS and ASD. You need MAO to break down dopamine, nor-epinephrine and epinephrine. You can find out how bad this is by using Dr Google to look at the side effects of MAO inhibitors. It is pretty bad and curiously it is very similar to many of the symptoms that are listed on the B12 deficiency symptom list that you can see at http://b12oils.com/deficiencyfrm.htm If you fill out the form I can let you know which of the symptoms may be entirely due to MAO. To overcome this you need to supplement with lots of vitamin B2, BUT you need to have an active thyroid function to do this as you can't turn B2 into FAD and FMN if you thyroid is not working well.

My suggestion, you need 5MTHF and folinic acid if you can get it. Split the doses so that you get a smaller dose 2 x per day.

You need to sort out your thyroid function as many of the CFS like symptoms are due to low FAD. You thus need to take vitamin B2 and have normal thyroid. The fact that you reacted so strongly suggests that you are a bit out of whack. You also need it to help MTHFR, MTRR, MAO, and DAO and NOS. Oh FAD is also in the one enzyme that is common in CAC and your eletron transport chain. You won't get good energy transfer if you are low in vitamin B2.

If you have found that the sub-lingual AdoB12 was working then you should do well on the Ado/MeCbl mix.
Keep up the vitamin D3 and sun-baking. The higher the levels the better. Oh and I did find VDR Taq mutation, which means that you have trouble keeping vitamin D3 in your body, so the effect of low vitamin D3 will be worse for you.

 

[MrME/CFS++]

Just to clearify this for everybody, I read somewhere that there is a greater odds of beeing compound heterozygous for C677T and A1298C than not beeing it. It has to do with something that these two poly's came from two different persons back in time.

Can someone confirm that this is true or not?

Here are the statement: "Odds are that you inherited C677T from one parent and A1298C from the other. There are exceptions where you could have gotten both from one parent but these are extremely rare."

and here are the link to the site: http://genetics.thetech.org/ask-a-geneticist/mthfr-a1298c-c677t

If this is true it will be more people out there with compound variants than I thought from the beginning. I feel this persons explanation is convincing to me.

 

[Valentijn]

Just to clearify this for everybody, I read somewhere that there is a greater odds of beeing compound heterozygous for C677T and A1298C than not beeing it. It has to do with something that these two poly's came from two different persons back in time.

He claims "For starters, geneticists have looked at thousands of people for these two DNA polymorphisms. What they discovered was that if one copy of the MTHFR gene had C677T, it would rarely have A1298C also." but fails to provide any link to the claimed evidence.

His logic-based explanation doesn't really hold up either, I think, since it seems to be entirely based on assumptions that 1) the mutations evolved in a manner which was completely isolated from each other and 2) that the two sections of MTHFR including each mutation would therefore be unlikely to be inherited together.

If he's going to make such claims, he needs to cite to some solid sources.

 

[MrME/CFS++]

I can see that the statements not are done with evidences.

Her is another female student/genticist from Standford University who "claims" how odds are greater of beeing compound than not if your got both SNP's 677 and 1298. In this case the student/geneticist writes "The bottom line is that you and your husband almost certainly are compound heterozygotes. In other words, you each have one copy of A1298C and one copy of C677T (click here to find out more about A1298C and C677T)."

Also here the person dont use much evidences.

Here are the link: http://genetics.thetech.org/ask-a-geneticist/parent-genotype-child-genotype

I find it very odd that these two parents should be compound if being compund should be that rare in the population.

I dont know the answere, but are very interested in it. Also because I have both SNPs but dont know for sure if its is compound or not. I have all the discussed symptoms though...

I also find it odd that genetic students or geneticists does such statements on the university blog section if they not believe in what they write on the univeritys blog section. I asume that these people discuss the questions internaly with higher grade genticists before they post these answers to people.

The hole thing is a very very interresting thought spin.

We could ask everyone in this thread/forum if they are 100% certen that they are compound hetero for 677 and 1298 or not? If there is a high rate of proven compound it should indicate that being compound are more common than we all think, or not...

Another interesting question is if those with proven compound 677 and 1298 are diagnosed with ME/CFS.

Edit: Sorry for stating that these people was writing on the universitys blog site. I see now that it is on The Tech Museum of Innovation. Here is some disclaimer written on the site: "This project was supported by the Department of Genetics, Stanford School of Medicine. Its content is solely the responsibility of the authors and does not necessarily represent the official views of Stanford University or the Department of Genetics.". I have found out that the person from the first case was graduated from Standford School of medicine. Have not checked the other person.

 

[Valentijn]

I find it very odd that these two parents should be compound if being compund should be that rare in the population.

Just to clarify ... they're saying that having both mutations on the same strand (from the same parent) is uncommon. Being compound heterozygous, on the other hand, means having each mutation on a different strand.

But yes, still no good evidence provided, and their reasoning doesn't seem to hold up.