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.