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Revision of the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS

maddietod

Senior Member
Messages
2,859
Hi, determined.

In the past, the Pall protocol focused primarily on antioxidants. More recently, Prof. Pall has changed his protocol to include 5-MTHF together with hydroxocobalamin, so I would say that the treatments are pulling together more. He believes the results of our clinical study, but his view is that we have interpreted them incorrectly. He believes that the role of hydroxocobalamin is to scavenge nitric oxide, and the role of 5-MTHF is to scavenge peroxynitrite. Nitric oxide and peroxynitrite play major roles in his "NO-ONOO theory."

Best regards,

Rich

Rich, if it's not privileged information - Do you know how much hydroxyb12:5-MTHF Prof. Pall uses? Because that could easily be my next experiment. I've just moved my dose of Metafolin up to 1600mcg/day, and haven't yet added a b12.
 

richvank

Senior Member
Messages
2,732
Rich, if it's not privileged information - Do you know how much hydroxyb12:5-MTHF Prof. Pall uses? Because that could easily be my next experiment. I've just moved my dose of Metafolin up to 1600mcg/day, and haven't yet added a b12.

Hi, Madie.

I think Marty's current recommendations are here:

http://www.allergyresearchgroup.com/proddesc/discuss/MartinPallAntioxidantSuggestions.pdf

Looks like 1,000 micrograms per day of a new form of 5-MTHF and 60 micrograms per day of hydroxocobalamin. Looks like there would also be 800 micrograms per day of folic acid.

Best regards,

Rich
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Rich, that interactive diagram you posted a link to got me thinking: has anyone tried serine to try to boost conversion of homocysteine to cysteine? I have seen similar diagrams, but this time the serine leapt out at me. Bye, Alex

PS This might be another reason why meat eaters sometimes do better: serine is an amino acid.
 

richvank

Senior Member
Messages
2,732
Hi Rich, that interactive diagram you posted a link to got me thinking: has anyone tried serine to try to boost conversion of homocysteine to cysteine? I have seen similar diagrams, but this time the serine leapt out at me. Bye, Alex

PS This might be another reason why meat eaters sometimes do better: serine is an amino acid.

Hi, Alex.

I don't know. Sometimes serine is low on amino acids panels of PWMEs. I think it's usually because of low B6, because B6 is needed for transamination reactions, and serine is a nonessential amino acid, which can be made in the body. I frequently find low B6 on these panels, and I think it's because PWMEs burn amino acids for fuel more than normal, and transamination reactions are needed to feed the into the Krebs cycle beyond the partial block at aconitase. (Actually, voner was the one who posted that link.)

Best regards,

Rich
 

maddietod

Senior Member
Messages
2,859
Hi, Madie.

I think Marty's current recommendations are here:

http://www.allergyresearchgroup.com/proddesc/discuss/MartinPallAntioxidantSuggestions.pdf

Looks like 1,000 micrograms per day of a new form of 5-MTHF and 60 micrograms per day of hydroxocobalamin. Looks like there would also be 800 micrograms per day of folic acid.

Best regards,

Rich

I see 120mcg hydroxyb12 and 1600mcg folic acid - 2 multis twice a day. That's an amazingly small amount of b12! And it's swallowed. Interesting.

Thanks

Madie

edit: I did the math wrong. Rich's numbers are correct.
 

richvank

Senior Member
Messages
2,732
I see 120mcg hydroxyb12 and 1600mcg folic acid - 2 multis twice a day. That's an amazingly small amount of b12! And it's swallowed. Interesting.

Thanks

Madie

Hi, Madie.

I think the dosages for MVA are specified for a serving size of two capsules, so two capsules twice a day would be 60 and 800, rather than 120 and 1600, I think.

Yes, it is a low amount of B12, and it is swallowed. At one time, Marty told me that they were working on a liposomal hydroxocobalamin, as I recall, but I don't see it in his current protocol.

Note also that there is quite a bit of folic acid, which could compete for transport with the 5-MTHF.

I think Marty is focusing on using this new form of 5-MTHF to scavenge peroxynitrite, and he may be less concerned about scavenging nitric oxide, which is what he has emphasized that hydroxocobalamin will do. As you may know, he has a different theory for the pathophysiology of ME/CFS, and peroxynitrite plays a big role in it. He does not buy into the functional B12 deficiency.

Best regards,

Rich
 

redo

Senior Member
Messages
874
Hi, all.

I have made a revision to the GD-MCB hypothesis based on recent discussions with Prof. Martin Pall. The revised version is below. The important change is shown at number 5 below. In the past, I had hypothesized that the folates were depleted by the so-called "methyl trap" mechanism. Marty Pall has convinced me that this explanation does not fit the observation that the plasma level of 5-methyltetrahydrofolate (5-MTHF) decreases in ME/CFS patients, rather than increasing, which would be expected from the methyl trap mechanism. It has been shown by Antoniades et al. that 5-MTHF will react with peroxynitrite, and there is some evidence that peroxynitrite does rise in ME/CFS, as would be expected from the well-documented state of oxidative stress in this disorder. Reaction with peroxynitrite would be consistent with the observed lowering of plasma 5-MTHF. Therefore, I agree that this is currently the most plausible explanation for the loss of folates from the cells in ME/CFS, and I am therefore modifying the GD-MCB hypothesis accordingly.

This does not impact treatment based on the GD-MCB hypothesis, but it does give a better match to the observations.

Best regards,

Rich


Revised Summary of the Glutathione DepletionMethylation Cycle Block Hypothesis for the Pathogenesis and Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Rich Van Konynenburg, Ph.D.

January 13, 2012

1. There is a genetic predisposition toward developing ME/CFS, only part of which has been characterized.

2. Some combination of a variety of stressors (physical, chemical, biological and/or psychological/emotional), the combination differing from one case to another, together with the genetic predisposition, lead to depletion of glutathione by several mechanisms, including oxidative stress, conjugation by toxins, and depletion of amino acids needed for synthesizing glutathione.

3. The depletion of glutathione causes a functional deficiency of vitamin B12, so that both methylcobalamin and adenosylcobalamin become depleted.

4. The depletion of methylcobalamin inhibits the activity of the enzyme methionine synthase in the methylation cycle, producing a partial block.

5. Peroxynitrite, which rises as a result of the glutathione depletion, reacts with methylfolate, lowering the intracellular folates in general.

6. The partial block of the methylation cycle also deranges the sulfur metabolism in general and stabilizes the depletion of glutathione by a vicious circle mechanism, making ME/CFS a chronic condition.

7. The many abnormalities and symptoms of ME/CFS stem directly from the several aspects of this vicious circle mechanism.

First I'd like to point out that I think that methylation issues are key to understanding CFS (and IMO several autoimmune conditions in general), so the reason I ask is not to be critical.

What I wonder, is how the methylation theory explains the increase in prevalence of both CFS and autism in the Western world? If one would assume that it's not only better diagnostics which is causing the syndromes to be more and more prevalent.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
First I'd like to point out that I think that methylation issues are key to understanding CFS (and IMO several autoimmune conditions in general), so the reason I ask is not to be critical.

What I wonder, is how the methylation theory explains the increase in prevalence of both CFS and autism in the Western world? If one would assume that it's not only better diagnostics which is causing the syndromes to be more and more prevalent.


Hi Redo,

Incidence of all manner of neurological disorders in the industrialized vitamin taking vitamin enriched foods and baby formula part of the world. These climb with the rate of cycbl, hycbl and folic acid replacing the real vitamins. I think that methylation deoesn't get blocked the same way if people have mb12 and adb12 and natural folates in their foods. The smaller incidence of 60 years ago would have been limited to people with actual deficiencies of these things caused by eating/absorbtion problems or natural paradoxical folate deficiency. Now it has all those same people plus those who have paradoxical folate deficiency and paradoxical b12 deficiency who can't assimilate the inactive vitamirs that have replaced the natural ones.

These are man made deficiency diseases just as beri-beri and pellagra were created by the roller mill making perfect white flour or scurvy from long sea voyages on limited incomplete foods.

So I think that methylation theroy is an excellent fit since a broken methylation system is a major effect of inactive cyanocbl, hydroxycbl, folic acid and for some folinic acid. Broken methylation, whether of the "partial block" theory or "depleted methyaltion capacity" theory or whatever variations is a mjor effect of lack of mb12/methylfoalte. The crippled mitochondria is often from the lack of adb12, the other major leg of rthese many broken system diseases.