Hi, Caledonia.
You've raised a lot of good questions. I've addressed most of the issues you've raised in my papers starting in 2004, which can be found on Cort's site at
http://aboutmecfs.org.violet.arvixe.com/Trt/TrtGSHIntro.aspx
However, I will try to hit the high points here.
Genetics: I believe that there is a genetic predisposition to ME/CFS, for several reasons: There have been twin studies and family tree studies that point to this being the case. There are SNPs that have been found at higher frequency in PWCs than in the general population. There has to be a reason why everyone doesn't get ME/CFS. It appears that it is not just one SNP that is involved in this genetic predisposition, but a set of SNPs that affect the same biochemical pathways. As you noted, the set is not the same for everyone, but the collection of them impacts the same certain pathways in all the PWCs. It's the overall impact on the pathways that matters. Which pathways? This isn't completely nailed down yet, but I think the methylation cycle, folate metabolism, and glutathione system are most likely involved. Perhaps the detox system, the wider antioxidant system, the immune system (including the HLA genotypes), and the stress response systems would be good candidates for inclusion, too. I wish we had more data on polymorphisms in the enzymes and other proteins in all these systems. If we did, I think we could answer this question.
In addition to the genetic predisposition I have suggested that some combination of a variety of stressors, which can be physical, chemical, biological and/or psychological/emotional is necessary to bring about onset of this disorder, and long-term stressors seem to be particularly devastating in this regard, as you suggest. I believe this for several reasons. First, I have received histories from many PWCs, and the events that preceded the onset of their illnesses featured this whole range of stressors, and in many cases, they were piled on top of each other, as in a "perfect storm." Second, I have studied the published "risk factor" studies for ME/CFS and they show the same thing. Third, it is a fact that the body deals with this whole variety of stressors by means of the nonspecific stress response systems (in addition to making specific responses to the various stressors). The nonspecific stress response systems come down to secreting cortisol, epinephrine, and norepinephrine.
When these substances are at high levels for long times, the result is a major demand on glutathione. This seems to be a unifying feature. Furthermore we have measured glutathione in many PWCs now, and it is usually depleted. If not, it seems that there are SNPs in the enzymes that use glutathione, giving much the same result. Glutathione is at the basis of the antioxidant enzyme system, so when it goes down, oxidative stress ensues. Oxidative stress is probably the best documented biochemical abnormality in ME/CFS.
It is known that one of the roles of glutathione is to protect vitamin B12 from reactions with toxins. When glutathione is depleted, B12 is unprotected, and a functional deficiency in B12 results. This is evidenced by a rise in methylmalonate, and we have seen this in a large number of PWCs by now.
When B12 becomes functionally deficient, it is unable to perform its two roles in the body. One of these failures gives rise to methylmalonate. The other robs methionine synthase of its necessary coenzyme, methylcobalamin. When that happens, this enzyme becomes inhibited, and both the methylation cycle and the folate cycle experience a partial block. This shows up directly on the methylation panel, and it also shows up as a rise in figlu on the urine organic acids panel.
What about XMRV? There's a lot we don't know about this yet. However, we do know that methylation silences the expression of retroviral genes, and we also know that glutathione favors viral activity in general. A partial block in the methylation cycle and glutathione depletion would favor the retroviruses. It is possible that they have developed ways of bringing this about. It could also be that they rely on their "cousins," the herpes family viruses or other viruses that survive in the body in the latent state, to do this for them.
With regard to Marty Pall's model, my opinion is that it is subsumed within the model I have proposed. In other words, I believe that the reactions he discusses do occur, but they result from the partial block in the methylation cycle, rather than being the cause of it. The stressors he mentioned all place demands on glutathione. I think it's likely true that nitric oxide rises, but I think that's result of the lowered production of assymetric dimethyl arginine, which is normally the main inhibitor of nitric oxide synthase. A partial methylation cycle block causes less production of this inhibitor, and that allows nitric oxide to rise. Peroxynitrite also rises, but I think this is mainly a result of the rise in superoxide, which reacts with nitric oxide to form peroxynitrite. Superoxide rises because of glutathione depletion, which produces a rise in hydrogen peroxide, and that causes superoxide to rise.
It's true that some of the stressors are short term stressors. However, if the load of stressors is severe enough, a vicious circle can become established. This is an unnatural positive feedback system that perpetuates itself. I have suggested that the combination of glutathione depletion and a partial methylation cycle block is the vicious circle that causes ME/CFS to be chronic. I think this is supported by the observation that when methionine synthase is supported with high-dose B12 together with active folate, both the methylation cycle partial block and glutathione depletion are observed to be corrected.
When this system is operating normally, short term stressors that cause oxidative stress do temporarily shut down methionine synthase, and this causes more of the homocysteine to be diverted into the transsulfuration pathway, to make more cysteine, which can be used to make more glutathione, to counter the oxidative stress. Once this problem has been overcome, methionine is allowed to resume converting homocysteine to methionine. In ME/CFS, this normal regulatory function is driven out of operation, and the system gets "stuck" in a vicious cycle. But it can be restored to normal by boosting methionine synthase with simultaneous active, reduce folate, and high dose B12.
Best regards,
Rich