To freddd (and the group).
I'm the guy who (about two and a half years ago) extracted (with the help of a person who has CFS) part of step 2 of Amy Yasko's treatment program (primarily used in autism), called it the "Simplified Treatment Approach," and suggested that it be tried as a treatment for CFS. This protocol includes five supplements. The main B12 supplement is sublingual hydroxocobalamin. It also includes both 5-methyl tetrahydrofolate and folinic acid.
I've studied the extensive posts that you've made to this forum, and I'm aware of your position on which forms of B12 should be used, and which should not.
Let me just say up front that I find what you've done very impressive, and I imagine that it has helped (and expect that it will help) a lot of people.
Since quite a few people have been raising questions about our apparent differences, I think it behooves me to make some comments here, for what they are worth.
I want to acknowledge that I realize that I have a lot to learn about all of this, and I want to say that my goal is to try to find the truth, and to use it to help as many people as I can to recover from CFS. I'm not motivated to try to defend a hypothesis for the sake of trying to be "right."
So I hope you will view what I say in that light.
The first thing I would like to clarify is the distinction between an inborn error of metabolism (IEM), which stems from a rare and serious inherited genetic mutation, and an acquired syndrome. Chronic fatigue syndrome, by its case definition, is an acquired syndrome. In the words of the Fukuda et al. case definition, the fatigue must be "of new or definite onset (has not been lifelong)". An IEM, on the other hand, is by definition "inborn," i.e. lifelong. There is evidence for a genetic component to the predisposition to developing CFS, but the syndrome itself is not apparent in the first part of the person's life. I realize that this is just a consensus definition, and it has many problems, but nevertheless, this is what it says, and people who have been diagnosed on the basis of this definition do not have a lifelong illness.
From what you have posted, Fred, I understand that you have an IEM that involves the genes that code for one or more of the cobalamin processing enzymes. On the other hand, the people to whom I proposed the "Simplified Treatment Approach" have chronic fatigue syndrome.
As you may know, while this number varies depending on which definition of CFS is used, and is the subject of current debate, the prevalence of CFS as defined by the Fukuda et al. definition has been estimated at about 0.4% of the population by Jason et al., which would amount to over a million people in the U.S. alone.
I have not been able to find published data on the prevalence of the cobalamin processing-related IEMs. I've read that cblC is the most common of them, and that it is "rare." I'm not sure how rare. One source, dated in 2006, reported that there were a total of 250 known cases.
My point here is that only a very small fraction of people with CFS can possibly have the IEM that you inherited.
In pointing this out, I am in no way trying to minimize the severity or the importance of your condition. As you pointed out, you are fortunate to be alive, given the experience of many people who inherited the IEM that you have. I do want to suggest, though, that these two are different, and that there is not much comorbidity between these two disorders. As such, though much of what you have learned in treating your IEM may apply to the treatment of CFS, there are likely also some differences.
You have emphasized that in the treatment of your disorder, it has been necessary to use large dosages of methylcobalamin and adenosylcobalamin, and that other forms of cobalamin, such as hydroxocobalamin, are not useful. According to my understanding of the IEM that you have, you are absolutely right about that, and the fact that you have found this out is vital to your regaining your life.
However, for those who do not have these IEMs, which as I've indicated above would include the vast majority of those who have CFS, other forms of B12 are useful. In fact, recent research (PMID: 19447654) indicates that whatever the form of cobalamin, when it enters a cell in the normal way, the first thing that happens is that the beta ligand (whether cyano- hydroxo-, aquo-, methyl-, or adenosyl-) is removed from the cobalamin molecule by the cblC enzyme, before the cobalamin goes on to be converted to either methylcobalamin or adenosylcobalamin. So in the case of a person who does not have these IEMs, any form of cobalamin can be used to produce the two active coenzyme forms. These researchers did find, however, that the initial form of the cobalamin did have an effect on the relative amounts of methyl- and adenosylcobalamin that were formed. Based on this, I do not think it is valid to state that hydroxocobalamin cannot be used in the treatment of CFS.
You have made the point that use of methylcobalamin and adenosylcobalamin should, however, suffice for treating any of these B12-related conditions, including the IEMs and CFS. I agree that this is true, but I have one concern with use of high dosages of methylcobalamin in CFS. It relates to the fact that many people who have CFS have had amalgam fillings in their teeth during many years of illness, during which glutathione has been depleted in their bodies. It is likely (and there is evidence to support this) that these people have significant body burdens of inorganic (mercuric) mercury. It has been shown that methylcobalamin has the capability of converting mercuric mercury into methylmercury, and it has also been shown that methylmercury is able to cross the blood-brain barrier readily, thus delivering a major neurotoxin into the brain. I am concerned about this. I have heard of two cases in which high dosages of methylcobalamin were applied intravenously in the presence of significant apparent body burdens of mercury, and in both cases, the people reported what seemed to me to be symptoms of neurotoxicity shortly afterward.
Do I have quantitative evidence to show that this is a problem? No, I don't. Methylcobalamin is used a lot in autism, as advocated and practiced by Dr. James Neubrander. However, babies and young children do not usually have amalgam fillings. The bulk of the mercury they have received, such as from thimerosol in vaccinations, has been organic ethylmercury, which unfortunately has already had a chance to enter the brain.
When sufficiently large dosages of methylcobalamin are given, as you have noted, the carrying capacity of the transcobalamin carrier protein in the blood plasma is saturated, and the excess methylcobalamin exists for a time in the blood as free molecules. It is this methylcobalamin that concerns me, in terms of its capability to react with mercury. I realize that you need to do this to get enough methylcobalamin into your cells, given your IEM, but this is not true for the majority of people with CFS, and I think there is a risk in doing it this way if there is much inorganic mercury present. I can't prove that this is a problem, but I'm concerned that it might be.
Incidentally, I am not a fan of using large dosages of cyanocobalamin, either. I know of one case where the person developed cyanide toxicity from the use of milligrams-level daily dosages of cyanocobalamin in the presence of depletion of all of the body's mechanisms for detoxing cyanide.
I would also like to comment on glutathione. You have emphasized that adding glutathione torpedoes your ability to make use of methylcobalamin. I can understand this, since it will react to form glutathionylcobalamin, and given your IEM, your body is not able to convert this back to methylcobalamin. However, for the great majority of people who have CFS, this is not a problem, and in fact, if my hypothesis is correct, the lack of enough glutathione to form glutathionylcobalamin, which normally protects cobalamin from reacting with toxins at an intermediate stage of its processing in the cell, is at the root of the pathogenesis of CFS. As I noted in an earlier post that was relayed to this board, glutathione is not part of the Simplified Treatment Approach, but some people have added it and found that it has been beneficial. Others report that they cannot tolerate it. I'm not sure why, but suspect that it raises either cysteine or sulfite too much in some people. Adding molybdenum has helped some people, suggesting that sulfite was the problem in those cases.
Well, I just wanted to make those points. It is not my desire to be argumentative, and I certainly do not want to discourage you from helping a lot of people. I'm willing to listen, and hopefully learn, from any response you might want to offer on these issues. I just wanted to try to clear up differences, to the degree possible.
I wish you the best.
Rich Van Konynenburg