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Methylation Cycle Questions -- Need Help Deciphering Symptoms

O

OneToughCanary

Messages
25
Hello,
Is there a post somewhere that gives a handy outline of what symptoms indicate a need for what in relation to the methylation cycle? I'm having some success with tackling my health issues from that angle -- getting my methylation cycle going, which had evidently all but died -- but it's herky-jerky, trial-and-error as I I try to figure out when my body's crying for B12, when it needs Mfolate, when it needs niacin because methyl is piling up, when it's low on electrolytes because things are starting to "go" in my body and are using up electrolytes, when it's crying for methionine because it didn't have enough before starting Mfolate. I've read articles like Ben Lynch's here...

http://mthfr.net/preventing-methylfolate-side-effects/2014/11/26/

...but I could really use lists of "If you have this symptom the cycle is probably stalled here____and you need _____." I've gotten snippets from posts I've come across, but with my brain fatigue it's hard to follow it all. A "symptom navigator" that cuts to the chase bullet-point style would be so helpful. Is there a post or webpage someone could direct me to for something like that?
Thanks,
OneToughCanary
 
R

robinhood12345

Senior Member
Messages
151
The essential nutrient choline actually starts the methylation cycle

n4ntj33.png


From here
http://sci-hub.tw/https://doi.org/10.1002/bdd.1892

And choline deficiency is common so that is something to consider.
 

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A

alicec

Senior Member
Messages
1,572
Location
Australia
robinhood12345 said:
The essential nutrient choline actually starts the methylation cycle
Click to expand...

You are misinterpreting the diagram. Since the paper is about choline transporters, this is the only uptake mechanism shown. It doesn't mean it is the only one operating. Uptake of many others substances, most notably methionine and methyl folate, is also very relevant to the methylation cycle.

At the heart of the methylation cycle is the remethylation of homocysteine to produce methionine, which in turn is the precursor of S-adenosyl methionine (SAM), the universal methyl donor in hundreds of reactions in the cell.

In the cell, this reaction proceeds in two ways.

In one pathway, betaine (derived from choline) donates the methyl group needed to produce methionine from homocysteine,catalysed by the enzyme betaine homocysteine methyltransferase (BHMT).

In the other pathway, methyl B12 donates the methyl group (which ultimately comes from methyl folate), catalysed by the enzyme methionine synthase (MTR).

Overall, there is a roughly 50:50 contribution from the two pathways, but this varies greatly among tissues. BHMT is expressed only in liver and kidney while MTR is widely expressed in many tissues.
 
O

OneToughCanary

Messages
25
First of all, thanks for the responses. Secondly, I know some forums request that you not send "Thank You" responses, so as to not clutter up the forum. Is that the preference here, or are thank-yous appreciated?
OneTough
 
Mary

Mary

Moderator Resource
Messages
17,365
Location
Southern California
OneToughCanary said:
First of all, thanks for the responses. Secondly, I know some forums request that you not send "Thank You" responses, so as to not clutter up the forum. Is that the preference here, or are thank-yous appreciated?
OneTough
Click to expand...
"Thank you" posts are fine, and I think are appreciated :)

But if someone simply agrees with a post or likes it, then it's recommended that they hit the "like" button, instead of doing a separate post.

A tip for you: If you are responding to someone, you can either hit the "reply" button, which will alert the member you're responding to their post, or you can tag them by putting the "@" sign in front of their user name, like this @OneToughCanary or this @Mary. If you are replying to a lengthy post, it's recommended that you select the text you are replying to by highlighting it, and then an option will pop up to let you reply to the selected text. Sometimes posts are very lengthy so it saves clutter.
 
A

alicec

Senior Member
Messages
1,572
Location
Australia
OneToughCanary said:
this post looks amazing.
Click to expand...

Just be aware that many of the so-called facts about methylation are based on misinterpretation of research or are contrary to research or are not based on research at all - ie just made up. Many of the gurus just endlessly repeat the same misinformation.

You need to be discerning and sceptical in your reading, particularly on sites that are trying to sell you supplements (eg Lynch and Yasko).

See the following posts to get an idea of what you should and shouldn't be looking for - here, here, here, here, here, here.
 
O

OneToughCanary

Messages
25
@alicec Thank you for the heads-up for avoiding misinformation. I get a little lost in the technical talk. Could you help me get my brain around the main take-away from this? I'm gathering that perhaps the need to hyper-analyze one's SNPs and add in this and that to juggle their supposed effects is overblown. (?) I.e, that this is simpler than it has been made out to be? If that's the case, could you direct me to what you feel is the most on-the-mark info and approach? Do you give Caledonia's links shared above a thumbs-up? (Caledonia, I appreciate the sharing regardless; I know we're all learning together.) Could you give me a quick bullet list of the key "facts" I'm likely to run into that are actually false or dubious?

(I don't know if I'm asking too much; just looking for a quick summary. I did read the links you sent; I just tend to lose my way in what to take home from what I read...other than the general reminder to be careful.)

Thanks,
OTC
 
caledonia

caledonia

Senior Member
Messages
4,610
Location
Where the land is hilly and they eat hot chili
OneToughCanary said:
@alicec Thank you for the heads-up for avoiding misinformation. I get a little lost in the technical talk. Could you help me get my brain around the main take-away from this? I'm gathering that perhaps the need to hyper-analyze one's SNPs and add in this and that to juggle their supposed effects is overblown. (?) I.e, that this is simpler than it has been made out to be? If that's the case, could you direct me to what you feel is the most on-the-mark info and approach? Do you give Caledonia's links shared above a thumbs-up? (Caledonia, I appreciate the sharing regardless; I know we're all learning together.) Could you give me a quick bullet list of the key "facts" I'm likely to run into that are actually false or dubious?

(I don't know if I'm asking too much; just looking for a quick summary. I did read the links you sent; I just tend to lose my way in what to take home from what I read...other than the general reminder to be careful.)

Thanks,
OTC
Click to expand...

At this time, I'm suggesting that people get Ben Lynch's new book "Dirty Genes" which emphasizes epigenetics over genetics. He spent 2 years researching the literature and has identified 7 major genes. Epigenetics are how your environment and lifestyle affect your genetic expression regardless of SNPs.

The idea of seeing that you have X SNP, so you need to take Y supplement is obsolete. SNPs are only potentials, and you only need to address them if they're expressed. Environmental influences can cause them to express.

He has laundry lists of symptoms that can help you identify if a particular gene is "dirty" and then suggestions on how to clean it up.

It's already been helpful to me in regard to the PEMT gene. Mine happens to be +/+, but it's also expressing with back pain in my right shoulder blade area, which is referred pain from the gall bladder. I had no idea. Gall bladder issues run in my family. So I've received an early warning signal that will hopefully prevent my gall bladder from getting worse. I've been following the suggestions and the pain is mostly gone.
 
A

alicec

Senior Member
Messages
1,572
Location
Australia
OneToughCanary said:
I'm gathering that perhaps the need to hyper-analyze one's SNPs and add in this and that to juggle their supposed effects is overblown. (?)
Click to expand...

Some SNPs, particularly in combination, may have particular relevance to the methylation cycle and mean that an individual might have some difficulties with the methylation cycle because of genetics.

I'm thinking here of MTR rs1805087 aka D919G aka A2756G, especially in combination with MTRR rs1801394 aka I22M aka A66G.

The MTHFR SNPs rs1801133 aka C677T and to a lesser extent rs1801131 aka A1298C are also relevant.

These SNPs have been shown to have significant effects on important enzymes in the cycle and so a person +/+ for one or more should definitely pay close attention to obtaining sufficient B12 and folate.

There are a couple of other less commonly cited SNPs which are known to affect other enzymes in the cycle. One former PR member Valentjin started a number of threads listing the SNPs which are known to affect enzymes in the cycle. You can search for them - usually titled Interesting X Variations (for X substitute the enzyme of interest - eg MTHFR).

The list of SNPs trotted out by Yasko and repeated on many sites analysing 23andme data as being relevant to methylation are simply not. Most do little or nothing. If you have such a list you can look for the genes in the Interesting Variations threads and find which SNPs actually have an effect.

What you need to understand is that all of these variants which have become the focus of internet chatter, even the ones known to have significant effects, are very common in the population. Many, many millions of people live with them and their bodies compensate perfectly adequately. They are not the cause of disease.

In some instances, particular when the system is under higher demand such as during pregnancy and in some illnesses, the body may not be able to compensate and it becomes particularly important to provide added support in the form of supplements.

In addition to the common variants, there are a number of much rarer variants which can have very serious effects on the cycle. An individual would need to do particular research on 23andme or exome data to identify these.

In any case, for the many individuals on PR who report benefit from supplementation of B12/folate and associated nutrients, their SNPs are unlikely to be the reason. At most, some combinations may be making a contribution.

It is much more likely that the widespread metabolic derangement associated with ME/CFS means that their illness is adversely affecting pathways which are stimulated by the supplements.

If you want to see if such supplements benefit you then give it a go with an open mind and not too many preconceived notions. Many of the explanations given about what things mean are just someone's theory.

Essentially start with low doses of B12 and folate (not folic acid) and increase slowly. Ensure you have adequate intake of all B vitamins and a wide range of other nutrients.

Be aware that many people find their need for potassium increases and that folate need might suddenly increase too. If unpleasant symptoms occur, try adding potassium gluconate and/or increasing folate and see if this helps. Niacinamide (not niacin) might be helpful in quenching unpleasant symptoms if you go too far with dose.

Many people have written about their experiences with methylation protocols. Caledonia gives some of those links. Reading some of those might give clues about what to expect.

Don't overcomplicate it, proceed slowly and listen to your own bodies responses. Adjust dose to suit yourself. It is not rocket science and there is no fixed recipe.

OneToughCanary said:
Do you give Caledonia's links shared above a thumbs-up?
Click to expand...

The links to other peoples experiences and descriptions of various protocols give good background, just don't think that their explanations for why things happen the way they do are necessarily correct. The Nutraeval stuff is very useful.

The links to SNPs explanations from people like Yasko, Lynch and Heartfixer are the things I am flagging as being full of misinformation.

And as for Lynch's latest foray into so-called epigenetics, well this is the worst of pseudoscience. I posted on that in a previous link I gave you.
 
O

OneToughCanary

Messages
25
@robinhood12345 Is it usually such that it makes a person need *more* choline, thiamine, and/or biotin? ...or more along the lines of meaning a person can't tolerate those?

Here are my SNPs -- any thoughts?

COMT 158+62+
Taq+
MAO 297+
MTHFR 677+ 1298+
MTRR 66+ 664+
BHMT 8+
AHCY 1+ 19+
CBS 699+

I'm still dealing with this odd skin thing (see other post), and I wonder if a deficiency in something is making me react to the MB12 with skin eruptions. (...although in the meanwhile I *am* trying the suggestion @alicec made to up my MFolate.)

Thanks for the help,
OTC
 
A

alicec

Senior Member
Messages
1,572
Location
Australia
OneToughCanary said:
Here are my SNPs -- any thoughts?
Click to expand...

The first COMT and the two MTHFR SNPs do slow the respective enzymes, though +/- would have a small effect.

With the two MTHFR SNPs, there is a 50:50 chance that these could be on opposite strands, ie compound heterozygous which would have the same effect as +/+. There is no way of knowing this because 23andme doesn't record which strand results come from.

Even so, as noted previously, many millions of people live with the +/+ condition without difficulty. Just ensure folate consumption is adequate.

The first MTRR SNP does have a small slowing effect which is more significant in combination with a MTR SNP which you don't have. +/- in isolation would have little consequence.

The second SNP can be protective - but Yasko's call on the risk allele is incorrect (and from this list, this analysis is based on SNPs Yasko was interested in - not something to be recommended). See this thread.

The BHMT SNP has a small effect which is protective since it reduces homocysteine.

The others have little effect.

I suggest you use Promethease or Enlis to get a more comprehensive view of your SNPs.
 
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