Would someone help me with my mutational interpretation?

[LaurieL]

This post kinda works on the requests for a Methylation 101 to be started here. I have been looking at my mutations, and I sure would like some input on if I am on the right track or not. I thought about whether this should be a private post or not, I just didn't want others to miss out on any information that could be helpful to them. Even if we all don't have the same mutations. I'm not asking for a diagnosis, just probabilites or areas in which attention might be needed considering this or that.

My only two +/+ mutations are the MAO-A and the MTHFR C677T.

The other mutations of any consequence are heterozygous, +/- and include:

CBS A360A
ACAT1-02
VDR Bsm/Taq
VDR fok
COMT L136L
MTRR
MTR
SHMT

Let me see if I understand this correctly, and for pete's sake, if I make a wrong statement, please correct it? I make many statements but they are also questions, looking for any input I can possibly get from anyone.

In a condensed form, my homework for each are as follows:

The MTHFR and you can add the vowels because I use them, is a down regulation, and with each +, becomes more of an issue. So a +/+ is a severe down regulation in which the basic purpose of the MTHFR is to make folate by converting 5,10 Mehtylene THF to 5 methyl THF.

SHMT is also a down regulation, and is what actually converts THF to 5,10 Methylene THF, the intermediate step before MTHFR.

An MTR mutation is an upregulation, in which it results in it always being on so it grabs every Hcy and 5 methylfolate molecule it can get ahold of and processes them directly to methionine and THF.

So if the above is correct, then due to my MTR mutation, not only is this pumping more THF in which SHMT cannot convert, nor can MTHFR convert, so I am overloaded with methionine and folic acid and severely deficient in 5 methylfolate, also called metafolin?

Since I only have a +/-, I realize the severity wouldnt be as much as if they were +/+ on all three fronts.

So whats happening then with SAMe and thymadine synthase? And due to the SHMT downregulation, am I making adequate purines?

The ACAT1-02 mutation can be the initial cause of Vitamin B12 deficiency, or is atleast associated with that? I dont know much about this particular mutation, except that it is involved in cholesterol production, of which mine is so very low, I dont even register at the low end of the scale. I believe it is also involved in biological production of energy but by which mechanism, I have no clue. And where is it located on a methylation cycle diagram?

With the MTRR mutation also in the B cycle end, would result in a double whammy effect on Vitamin B12 deficiency, because I cant make as much as I should, and any methyl B12 I might be making, gets sucked up by the upregulation of MTR and pumped right back to THF.

A COMT +/- would mean the propensity for excess methyl groups to exist, but in this case, my VDR Bsm/Taq +/- and my VDR fok +/- would actually result in my COMT acting like a COMT -/-. I also understand the L136L mutation is not considered to be a down regulation, and may perhaps be a compensatory mutation, or somewhat more beneficial than the others in COMT.

Soooo. A downregulation of MTRR and an upregulation of MTR =
low B12, high THF, low 5,10 Methylene THF.

???

The CBS mutation, is an upregulation, in which will drain methyl groups, and in consideration of the above, may explain my high tolerance to methyl groups?

What effects might all this have on my BH4 and urea cycle? I do have high ammonia that I have been fighting for quite sometime. I just cut out a big chunk of protein out of my diet, and am taking Yucca when I do eat protein.

So

COMT +/- and VDR +/- will behave as COMT -/- individual and are considered compensatory mutations. (Complimentary)

MTRR, regenerates methyl B12 and it is this mutation that leads to the greatest need to supplement methyl B12.

MTRs purpose is to regenerate folate.

VDR Bsm/Taq and fok are related to the neurotransmitters. I would like some more info on this, I dont have much on this. And isnt COMT involved with them as well, and how does my particular mutation fit in with the neurotransmitters. And then how do I fit that all in with the MAO-A +/+ mutation?

All the help I can get is so much appreciated. I tend to make statements as well, but actually most are questions and begging for feedback. TIA.

Laurie

 

[richvank]

***Hi, Laurie.

This post kinda works on the requests for a Methylation 101 to be started here. I have been looking at my mutations, and I sure would like some input on if I am on the right track or not. I thought about whether this should be a private post or not, I just didn't want others to miss out on any information that could be helpful to them. Even if we all don't have the same mutations. I'm not asking for a diagnosis, just probabilites or areas in which attention might be needed considering this or that.

My only two +/+ mutations are the MAO-A and the MTHFR C677T.

The other mutations of any consequence are heterozygous, +/- and include:

CBS A360A
ACAT1-02
VDR Bsm/Taq
VDR fok
COMT L136L
MTRR
MTR
SHMT

Let me see if I understand this correctly, and for pete's sake, if I make a wrong statement, please correct it? I make many statements but they are also questions, looking for any input I can possibly get from anyone.

In a condensed form, my homework for each are as follows:

The MTHFR and you can add the vowels because I use them,

***No, I can't believe you would do such a thing!

is a down regulation, and with each +, becomes more of an issue. So a +/+ is a severe down regulation in which the basic purpose of the MTHFR is to make folate by converting 5,10 Mehtylene THF to 5 methyl THF.

***It converts one form of folate to another.

SHMT is also a down regulation, and is what actually converts THF to 5,10 Methylene THF, the intermediate step before MTHFR.

***It's actually one of four reactions that can do that. The others use DMG, sarcosine, and glycine, respectively, while SHMT uses serine, as the one-carbon donor.

An MTR mutation is an upregulation, in which it results in it always being on so it grabs every Hcy and 5 methylfolate molecule it can get ahold of and processes them directly to methionine and THF.

***Well, at least it has more of a tendency in that direction.

So if the above is correct, then due to my MTR mutation, not only is this pumping more THF in which SHMT cannot convert, nor can MTHFR convert, so I am overloaded with methionine and folic acid and severely deficient in 5 methylfolate, also called metafolin?

***Please note that the SNPs produce tendencies, but what is actually going on biochemically may be influenced by other factors in addition to the genetics. If you have ME/CFS, your MTR reaction actually has a lower activity than normal, i.e. it is partially blocked, because it has insufficient methylcobalamin and 5L-methyl tetrahydrofolate supplied to it. The methylcobalamin is low because of glutathione depletion, which causes a problem in the metabolism of B12 within the cells, so not enough methylcobalamin is produced. The 5L-methyltetrahydrofolate is low inside the cells because it has drained out of them into the blood via the methyl trap mechanism, in response to the partial block of the MTR reaction. This pulls down the other folate forms, also, as they are converted to 5L-MTHF and it drains out. THF is low in ME/CFS, because the MTR reaction is partially blocked, and is not producing THF at a normal rate. Methionine often goes low, because it is not being replenished by the MTR reaction, and is lost when homocysteine drains into the transsulfuration pathway at a higher than normal rate.

Since I only have a +/-, I realize the severity wouldnt be as much as if they were +/+ on all three fronts.

So whats happening then with SAMe and thymadine synthase?

***If you have ME/CFS, your SAMe is likely lower than normal, because methionine will be low, as noted above, so there is less methionine to be converted to SAMe.

***Thymidine synthesis is low because the folates have drained out via the methyl trap mechanism.

And due to the SHMT downregulation, am I making adequate purines?

***Purine production is probably low also, because of the folate draining.

The ACAT1-02 mutation can be the initial cause of Vitamin B12 deficiency, or is atleast associated with that? I dont know much about this particular mutation, except that it is involved in cholesterol production, of which mine is so very low, I dont even register at the low end of the scale. I believe it is also involved in biological production of energy but by which mechanism, I have no clue. And where is it located on a methylation cycle diagram?

***The ACAT1 enzyme is not located in the methylation cycle. It is located in the mitochondria of the cells, and its function is to produce acetoacetyl-CoA from acetyl-CoA. Acetyl-CoA is used to feed the Krebs cycle, and it is made from carbohydrates, fats and amino acids that are used as fuel for producing ATP by the Krebs cycle and the respiratory chain in the mitochondria. Acetoacetate is one of the ketone bodies. It is produced when there is an abundance of acetyl-CoA, such as when fatty acids are the predominant fuel being burned. Dr. Amy has apparently found that a SNP in this enzyme affects the availability of B12, which is needed by the methylation cycle.

With the MTRR mutation also in the B cycle end, would result in a double whammy effect on Vitamin B12 deficiency, because I cant make as much as I should, and any methyl B12 I might be making, gets sucked up by the upregulation of MTR and pumped right back to THF.

***When MTRR is not working well, cobalamin cannot be restored to methylcobalamin as readily as normal, after it becomes oxidized, which happens every so often. So new methylcobalamin has to be supplied. Your double whammy concept is basically correct, though. These problems add up.

A COMT +/- would mean the propensity for excess methyl groups to exist, but in this case, my VDR Bsm/Taq +/- and my VDR fok +/- would actually result in my COMT acting like a COMT -/-. I also understand the L136L mutation is not considered to be a down regulation, and may perhaps be a compensatory mutation, or somewhat more beneficial than the others in COMT.

***I don't think the VDR Fok snp is involved here, but Dr. Amy has argued that the VDR Bsm/Taq does compensate for the COMT in the way you have described. I don't understand the biochemical basis for this, but it is something she says she has observed.

Soooo. A downregulation of MTRR and an upregulation of MTR =
low B12, high THF, low 5,10 Methylene THF.

???
***The SNPs are not the whole story. They give tendencies. With your combination, you will have a need for high B12 supplementation. Your THF is likely low, and your 5,10 MTHF is likely low, also.

The CBS mutation, is an upregulation, in which will drain methyl groups, and in consideration of the above, may explain my high tolerance to methyl groups?

***The CBS mutation will drain homocysteine from the methylation cycle more rapidly than normal, and will lower the concentrations of SAMe and SAH. I suppose that that would give you a high tolerance to methyl groups, because SAMe is the main donor of methyl groups, and it will likely be low.

What effects might all this have on my BH4 and urea cycle?

***Your BH4 will likely be low, because the biopterin cycle is linked to the folate metabolism, and it is depleted.

***The function of the urea cycle will depend on your status of amino acids as well as magnesium and manganese.

I do have high ammonia that I have been fighting for quite sometime. I just cut out a big chunk of protein out of my diet, and am taking Yucca when I do eat protein.

***I generally don't recommend going very low in protein in ME/CFS, because it is the main source of fuel for many PWCs, who are not able to burn carbs and fats well, because of glutathione depletion and the resulting partial block early in the Krebs cycle.

So

COMT +/- and VDR +/- will behave as COMT -/- individual and are considered compensatory mutations. (Complimentary)

***This is what Dr. Amy says.

MTRR, regenerates methyl B12 and it is this mutation that leads to the greatest need to supplement methyl B12.

***That's probably true. At least it does work in that direction.

MTRs purpose is to regenerate folate.

***Well, it reacts homocysteine with 5L-MTHF to form methionine and THF. So it closes the methylation cycle and also the folate cycle. It does double duty.

VDR Bsm/Taq and fok are related to the neurotransmitters. I would like some more info on this, I dont have much on this.

***This is something Dr. Amy has found. I don't know the biochemical basis for it.

And isnt COMT involved with them as well, and how does my particular mutation fit in with the neurotransmitters.

***COMT is used to break down the catecholamines (dopamine, norepinephrine, and epinephrine).

And then how do I fit that all in with the MAO-A +/+ mutation?

***MAO A is also used to break down neurotransmitters.

***Having these polymorphisms will give you a tendency toward abnormal neurotransmitter levels. These levels are also affected by other factors, such as the levels of the amino acids from which they are made, the level of BH4, and the levels of certain vitamins and minerals.

All the help I can get is so much appreciated. I tend to make statements as well, but actually most are questions and begging for feedback. TIA.

***I understand. These are good questions. Unfortunately the answers are not so straightforward. The genetic data gives information about tendencies, but it isn't straightforward to go from the SNP data to determining what's going on in the biochemistry, because that depends on other factors, also. That's why Dr. Amy also offers a package of biochemical tests. I prefer including the Health Diagnostics methylation pathways panel, which is a biochemical test. It will tell you what is actually going on in the methylation cycle, folate metabolism, and with glutathione.

Laurie

***Rich

 

[LaurieL]

Hi Rich,

I promise, I realize that the SNP's are not the whole story and are just tendencies. I can't thank you enough!! As far as the panel, I do want that, and I am trying to get it, but its just so far out of my reach. It would be a blessing indeed. So I wait, and I work every chance I get.

And yes, I very definately have CFS, and at one time MCS, of which the MCS has really improved exponentially, and the CFS I struggle on with. Please don't get me wrong, I have other diagnosis as well. I did share the previous history of 12 long years in the oncology unit for aggressive cholesteoma/destruction/mastoid/inner ear reconstructions, and my antibiotic chemo/multiple surgeries....saga. I don't want to go back there, and I don't think I would survive anymore surgeries considering my current problems.

I have more questions if that would be okay, I am really looking for some interaction and stand most appreciative. I am wiped after working so many doubles this week, so I need to go horizontal in a bad way. I really can't thank you enough for helping me to learn.

Laurie

 

[LaurieL]

***It's actually one of four reactions that can do that. The others use DMG, sarcosine, and glycine, respectively, while SHMT uses serine, as the one-carbon donor.

Rich,

Would you specifically name those reactions for me?

Laurie

 

[richvank]

Rich,

Would you specifically name those reactions for me?

Laurie

Hi, Laurie.

Yes.

DMG: dimethylglycine dehydrogenase

sarcosine: sarcosine dehydrogenase

glycine: aminomethyltransferase

serine: serine hydroxymethyltransferase (There are both mitochondrial and cytoplasmic versions of this enzyme.)

Best regards,

Rich

 

[tealady]

Hi Rich,
so where does the sulfur , alkaline urine mentioned in no 11 of one of your posts come into this cycle?

I had that in 2005, and around when taking a lot of B12 I think(but cant be 100% sure as of now)- I googled some old chats I had stored, but will have to go thru to see if I can find out anything of significance (lasted many months, maybe a year or two)..sorry bad memory. I will look it up more in a couple of weeks. Until I read that post of your I had NO idea anyone else had this. Used to burn my skin and I had to install a hand shower to wash straight away. Got some urine multi-test strips but pH wa the ONLY thing out in my urine. on the strips. I could not get anyone to test my blood pH. I used to wonder if my urine being so alklaine would mean my blood was acidic or alkaline... litmus paper with blood obviously doesnt work (as not clear enough). I had NO idea this was related to B12 intake, although I did start taking B1(y injections and thought that may have helped..but still unsure if I need or not as partt of the B12 protocol. I'd inject B1 and then B12.
I no longer have the alkaline urine, and it gradually went away. I'd have to check what I was doing then. will try to in a couple of weeks (sorry tax time here now).

PS I'm the one with the low ADH too, and I was trying to cut down the drinking then until this occurred too(specialist considered it was psychogenic-I didnt) I think.... again I'd have to check. I wish I had kept a hand written diary of everything instead of posting on various forums/chats/emails all over the web!

I just wanted to say I was very interested that this was something to do with B12, and any pathways are known for this to occur or enzymes lacking/nonoptimal?

 

[richvank]

Hi Rich,
so where does the sulfur , alkaline urine mentioned in no 11 of one of your posts come into this cycle?

I had that in 2005, and around when taking a lot of B12 I think(but cant be 100% sure as of now)- I googled some old chats I had stored, but will have to go thru to see if I can find out anything of significance (lasted many months, maybe a year or two)..sorry bad memory. I will look it up more in a couple of weeks. Until I read that post of your I had NO idea anyone else had this. Used to burn my skin and I had to install a hand shower to wash straight away. Got some urine multi-test strips but pH wa the ONLY thing out in my urine. on the strips. I could not get anyone to test my blood pH. I used to wonder if my urine being so alklaine would mean my blood was acidic or alkaline... litmus paper with blood obviously doesnt work (as not clear enough). I had NO idea this was related to B12 intake, although I did start taking B1(y injections and thought that may have helped..but still unsure if I need or not as partt of the B12 protocol. I'd inject B1 and then B12.
I no longer have the alkaline urine, and it gradually went away. I'd have to check what I was doing then. will try to in a couple of weeks (sorry tax time here now).

PS I'm the one with the low ADH too, and I was trying to cut down the drinking then until this occurred too(specialist considered it was psychogenic-I didnt) I think.... again I'd have to check. I wish I had kept a hand written diary of everything instead of posting on various forums/chats/emails all over the web!

I just wanted to say I was very interested that this was something to do with B12, and any pathways are known for this to occur or enzymes lacking/nonoptimal?

Hi, tealady.

I know of four sources of ammonia in the urine. First is the metabolism of amino acids, which produces ammonia as a byproduct. Second is the activity of certain bacteria in the gut, especially if dysbiosis is present. Third is the one identified by Dr. Amy Yasko, which is upregulating polymorphisms in the CBS (cystathionine beta synthase reaction). The latter also produces elevated sulfite. Fourth is the production of ammonia from glutamine by the kidneys, which is used to raise the pH of the urine if it is too acidic.

The urea cycle in the liver has the task of converting ammonia into urea, for excretion in the urine by the kidneys. If the production of ammonia is too high, and/or if the urea cycle is not functioning well, ammonia can rise in the urine.

When ammonia is elevated in the urine, it is important to test to see what the level of ammonia is in the blood, because high ammonia in the blood can cause serious problems for the brain (hepatic encephalomyelitis). In this case, physicians initially often give levulose, which is a sugar that is not absorbed from the gut. Bacteria in the gut ferment it to form lactic acid, which makes the pH in the gut more acid. That ties up ammonia (NH3) as ammonium ions (NH4+), which remain in solution and pass out in the stools. That prevents the ammonia from entering the blood. In the longer term, the cause of the high ammonia needs to be found and addressed, if possible.

Dr. Yasko has what she calls her "ammonia program" to deal with the CBS upregulation source of ammonia and sulfite. It is discussed in her book "Autiam, Pathways to Recovery."

Best regards,

Rich

 

[LaurieL]

Hi, Laurie.

Yes.

DMG: dimethylglycine dehydrogenase

sarcosine: sarcosine dehydrogenase

glycine: aminomethyltransferase

serine: serine hydroxymethyltransferase (There are both mitochondrial and cytoplasmic versions of this enzyme.)

Best regards,

Rich

Uhh.....yeah, but I was actually asking pathways, the reactions within a certain pathway. Obviously I wasn't clear...I was in a hurry... You must think I am a bubblehead... I was hoping this was something you knew and could fire right off the top of your head and save me some time in finding and learning it. I am just so time crunched as of late.

Tealady,

You mentioned going through something in which caused burning of your skin, and I believe you said sulfur and Rich mentioned ammonia. I swear I caught a sulfur smell the other day, but it was fleeting, and I am just not sure. I had ammonia problems, and that seems somewhat diminished. At least I can't smell it coming off of my person or in my breath. But the burning you mentioned. That is something new with me. I have been experiencing it for about a week. Also, my need for potassium has about tripled over the course of a few weeks. And that rash I broke out with when I started all this back in last October, its actually healing some more. And my conjunctivitis is diminishing, instead of goopy runny eyes, they now are less and a little more crusty like. Much improved. The continual thrush I have had for years is no longer present.

I just had someone last night at work ask me how I was feeling. They actually said for as late as it was, I looked fresh. Not dragged out, and my eyes were clear. They wondered what I was doing.

Laurie

 

[richvank]

Uhh.....yeah, but I was actually asking pathways, the reactions within a certain pathway. Obviously I wasn't clear...I was in a hurry... You must think I am a bubblehead... I was hoping this was something you knew and could fire right off the top of your head and save me some time in finding and learning it. I am just so time crunched as of late.

Tealady,

You mentioned going through something in which caused burning of your skin, and I believe you said sulfur and Rich mentioned ammonia. I swear I caught a sulfur smell the other day, but it was fleeting, and I am just not sure. I had ammonia problems, and that seems somewhat diminished. At least I can't smell it coming off of my person or in my breath. But the burning you mentioned. That is something new with me. I have been experiencing it for about a week. Also, my need for potassium has about tripled over the course of a few weeks. And that rash I broke out with when I started all this back in last October, its actually healing some more. And my conjunctivitis is diminishing, instead of goopy runny eyes, they now are less and a little more crusty like. Much improved. The continual thrush I have had for years is no longer present.

I just had someone last night at work ask me how I was feeling. They actually said for as late as it was, I looked fresh. Not dragged out, and my eyes were clear. They wondered what I was doing.

Laurie

Hi, Laurie.

I'm glad to hear that something good seems to be happening for you.

The four reactions I mentioned are in the folate cycle. All but the cytosolic form of SHMT are located in the mitochondria of the cells. They each contribute to converting THF (tetrahydrofolate) to 5,10-methylene tetrahydrofolate. Which one is most active depends on the concentrations of the various substrates that they use. I think that the SHMT reaction is usually the dominant one, and that is the one usually shown on pathway diagrams, but the others can contribute, too. The sarcosine dehydrogenase reaction is important when a person has a meal that contains a lot of meat, bringing in a lot of methionine in a short time. That causes a rapid production of SAMe from the methionine, and the glycine N-methyltransferase reaction then kicks in to skim off excess methyl groups from SAMe and give them to THF in the folate cycle via the sarcosine dehydrogenase reaction. They then can be given back to the methyation cycle later when methionine is a little lower, via the conversion of THF to 5,10 methylene tetrahydrofolae, which MTHFR then converts to 5L-methyltetrahydrofolate to feed the methionine synthase reaction, producing more methionine.

Rich

 

[LaurieL]

Rich,

Is the MAO-A +/+ an upregulation or a down regulation? Having this tendency would then predispose an individual especially in long term illness, to either high levels of neurotransmitters if this were activated or if upregulated, low levels of neurotransmitters?

I seem to be coming up with conflicting information.

Laurie

 

[Ferrum]

Hi LaurieL ,
About gene functions , diseases caused by gene mutation you can find on omim.org . Just input gene name in search line .
How many years do you suffer of conjunctivitis ?

 

[triffid113]

Do not believe the literature that CBS causes low homocysteine...get a test and see if it is true for you. I have TWO homozygous CBS mutations and HIGH homocysteine (so it is not a drain but a plug). It costs about $60 to measure homocysteine and the correct value is 6.3...so what can be easier than to test and be sure. DHEA is what fixes my CBS genes and I follow Freddd's protocol and I have perfect homocysteine except during allergy season (I am working on an alternate protocol for that, but it uses up so much zinc (needed for methionine synthase) that it destroys my methylation, my stomach acid, my throid and adrenal output).

You can't control what you can't measure. Measure it and be sure.

 

[greenshots]

I think its important to know that just because homocysteine is normal, doesn't mean anything because there may be a CBS. AHCY mutations also lower homocysteine so can hide a CBS. On the other hand, having MTHFR C677, BHMT and, or, MTR/MTRR defects will all cause homocysteine to rise so just because a CBS defect is present, doesn't mean it can suck down all the extra Homocysteine, it just suggests your levels would be SUPER high without the CBS. Then there's the CBS downregulation that Yasko and 23&me don't test for. This is one of the contributing defects that keeps homocysteine trapped inside, causing more damage. Its been linked with alzheimers, which my dad had.

Its really not about just one defect or one enzyme as many people try to make it. So many get caught up with MTHFR or CBS or whatever when all of them have some amazing interplay and I don't pretend to understand it all. The point being, we don't know what we don't know yet and there'll probably be more to come. But don't put all your eggs in one basket because the baskets will change.

 

[greenshots]

I'm certainly not Rich and I can't explain the chemistry like he can but the MAO A ++ is a downregulation. When it works well, its just like the COMT, only it cleans up serotonin insteada dopamine and norepi. when its broken, it leaves serotonin in the cycle. for some reason, these people seem to need more serotonin instead of less, like you'd think. Yasko thinks its got to do with negative feedback telling other things down the line to slow down its production, when there's too much on hand. I guess this leads to some ups and downs in serotonin so people can be moodier, have OCD, and other things.

Rich,

Is the MAO-A +/+ an upregulation or a down regulation? Having this tendency would then predispose an individual especially in long term illness, to either high levels of neurotransmitters if this were activated or if upregulated, low levels of neurotransmitters?

I seem to be coming up with conflicting information.

Laurie