What You Need to Know About CFS/FMS and MTHFR Gene Mutation (Research Papers)

Many people don't know that I ran some of the earliest research looking at methylation and people who have chronic fatigue syndrome and fibromyalgia. And I've been asked about that. So I thought today I would tell that story and tell what we learned through that research and kind of what's happened since then. So let's get into it. At the time, which was now a number of years ago, we were just starting to be able to do tests through labs for particular single nucleotide polymorphisms or SNPs. And one of them that we could do fairly reliably was the MTHFR gene pairs. So we would get a report, and of course it didn't look at the whole cycle, but we'd be able to get a report on MTHFR and whether it was a normal or one of the types had one or 2 SNPs that were not like a normal gene. So one would be a heterozygous, 2 would be a homozygous, and there 2 primary ones that in the research appeared to be more related to pathology. And so those were the 2 that were reported out at that time. Now, I do have to say the world has really changed since then, and we went from just having a few SNPs that we could test through these labs to being able to do these large SNP arrays and look at reports that have almost too much information about them. And those are very useful as well. But I think this has both some clinical and historical context for people with chronic illness, really. And so what I want to do is you kind of what happened with all that. Well, what led to doing this research in the first place was my practice has always been split between advanced chronic illness patients and advanced cancer patients. And in the advanced chronic illness part of the practice, we had taken over another practice that was 100% devoted to chronic fatigue syndrome and fibromyalgia patients who had a large population to work with. The next thing was we were just starting to be able to test for and really look at the importance and the relationship of methyl cycle problems specifically around the MTHFR gene, but also later, of course, related to other things in the methylation cycle. And at the time, I could only find one older paper from the 1990s that was done in Europe that did look at MTHFR. And I think it was chronic fatigue or fibromyalgia. I think it was chronic fatigue. And it said there was no correlation. But there really wasn't very much, and that had been quite a bit before the particular time we were working with. So we took a fairly robust group of patients, and we had a 2-step process with the research. So the first step of the research was to see if we had enough patients that had done testing for MTHFR and also had appropriately diagnosed either chronic fatigue syndrome or fibromyalgia. And if we took that group of people, the first question really was, Do they have any difference in incidence of MTHFR defects beyond the normal population in a matched setting? Now, what would we do to match? Well, MTHFR is obviously heritable. It's part of your genome. And so your cultural heritability has a lot to do with the quote unquote normal presence of MTHFR. So for example, certain cultural heritage would have almost no native MTHFR defects in them. Other cultural heritage would have, you know, medium and others would have a lot. And you find this with other things too. Well, as it turned out, the bulk of the patients we were testing were of genomic and cultural heritage that matched a very predictable amount in the normal population of that cultural heritage of MTHFR defects. So we had a standard to measure against. So if the normal population of this cultural genetic heritability has X percent MTHFR, do people of that same cultural heritability who have chronic fatigue fibromyalgia have the same amount of MTHFR in them? Or is there a higher persistence and presence in that group? So that was question number one, because if that showed no difference, then there was probably no connection to methyl cycle problems and chronic fatigue fibromyalgia type presentations. So that was our first question. So we found out the normal incidence in this population, and then we looked at the incidence in our patients who were diagnosed with chronic fatigue or fibromyalgia. And what we noticed was that the incidence in the sick group, the people with chronic fatigue, fibromyalgia, same genetic irritability, the incidence in the sick users were much, much higher, very statistically significant higher. So that was the first thing. So then the next question was, okay, we know it's more common to have methylcyclobutylamine But that doesn't mean that treating the system to support methyl cycle defects will do anything to help the overall health of these people who are ill. So part 2 of the study was the interventional part, and we did what is called an active comparator. So in the first part, we did a population comparison. So same heritability, one group is the overall population. What's the percent incidence and prevalence? The other group is a sick group who have particular illness. What's the incidence of MTHFR? Is it difference with the same genetic heritability? Indeed, there was difference higher in the sick group. The next part of the study was interventional, meaning we're going to give them something to help with their methylation and to support their genomic defect, and we'll see does it do anything because there were theories that it might do something, but there was really no data to show well an intervention would actually help these people. We knew they had more. Incidence of the genomic problem, but we had no idea what was on the other side of the door. So part 2, then we took the people and there was a majority of the people had one of the permutations of MTHFR. So we're looking primarily at 2 of the more pathogenic MTHFR SNP patterns, either C677, A1298. And those are the 2 big ones. And you could be heterozygous for one or the other, homozygous for one or the other, or an unusual combo called compound heterozygous, where you had one 1298 and one 677. So one of those patterns was within all of the people, and there were higher amounts of the more, you know, pathogenic combinations. So then what we did is we set up a particular intervention to help with the methyl cycle in these patients. And we already had baseline data on where they were. Symptomatically, uh, there's scoring that you can do, et cetera. And so the thing that these patients had in common is they'd been working with us anywhere from 1 to 5 years at this point. They'd all improved, but they'd all kind of plateaued. So our real question was, we know where they plateaued. Can we improve their health and their disease expression and their overall feeling of energy and, you know, all the things by intervening and treating essentially around their methyl cycle defects? And this was totally unknown. At the time, but we knew where they were stuck. And if we could get them to rise above that same scoring, we could show that the intervention did something. It's called a couple things, but active comparator, meaning you patient are your own baseline. So then I have the intervention group, which is a subset of the first group that was just the population control group, et cetera. And the sick group, smaller population, but we knew that they all had various methyl defects. And so each one of them were their own standard. So there wasn't a placebo control. It's a self-control. So if I am stuck at a score, I'm picking an arbitrary number, but let's say I'm stuck at a score of 42 out of 100, and 100 is robust health and 42 is not, but I came from a 12 up to a 42, but I can't get past 42. Then my comparator is, can I go from 42 to anything else with only this one intervention? So then we start the intervention and we already know what their genetic, you know, patterns are. And we did this over the course of a number of months and gave it enough time because it's a nutritional interventional protocol, gave it enough time to both manage them around the nutritional protocol, adjust doses, let it work, et cetera. But that was the new intervention. So your baseline is whatever you were stuck at. The new intervention's the only new thing added. And then at the end, when we reassess, we see, did we help your score improve more towards healthy or did it not improve. And what we found overall amongst all the different variations of methyl cycle defects is that the improvement was anywhere from about 54-55% improvement. So baseline to post-treatment, all the way up to 75+% improvement baseline to post-treatment. And that was across the board. No genetic variation had less than 54-55%. And as I say, it went all the way up to 75%. Well, what did we notice from all this? Well, the first thing was people with chronic fatigue fibromyalgia in our study had a much greater, meaning somewhere between 60 and 80% greater heritability of the more pathogenic variations of MTHFR patterns than their same heritability who were healthy. So you would have somewhere between 60 and 80% more of homozygous C677 or compound heterozygous, et cetera. And then it got less from there. When we treated everyone, the lowest amount of improvement was in the 50s, right? 54, 55%. But the people with the more pathogenic genetic variation, mostly homozygous C677, and then the compound heterozygous, had 60 to 75+ percent improvements over baseline in their overall scores. So in that group of people, not only did we show that people with chronic illness had more MTHFR problems than their heritable group with no illness. But also when we intervened and supported the whole methyl cycle, we improved their health somewhere between 50 and 75% over where they had plateaued. Now, this was really fairly, you know, groundbreaking information. I was invited to present it at a scientific meeting, which I did. But when you go to these things, you kind of get graded and the interest people have in that topic. Puts you either talking to a large group of people, talking to a small group of people, or being out with a poster and doing a poster presentation because they kind of can put lots of people in the poster area and we'll see what happens, right? Well, at the time, and if you think about it now, like this is really all the rage now and everybody's talking about you know methylation and genomics and all this stuff. At the time, it was a little bit on the front end of you know of medical intervention, let's say. And even though it was groundbreaking, we were put into category three. So I had to turn it into a poster and show the data. And I think that that evening we had a total of 2 or 3 doctors come by and look at the poster and talk about it. And the feedback I got from the meeting, the scientific meeting, was, well, genomics is not of great interest to physicians at this time. So we just don't think it's worth time, you know, in front of people, which just was sort of funny. It turned out though, that that was the base of a lot of information that then led to a lot of other clinical discussions and advancements and things like that. And interestingly, at the same time, there was a group partially from Harvard and some other universities that were in psychiatry, and they did a similar but much less broadly balanced therapy for people with treatment-resistant depression, meaning none of the drugs they gave them seemed to work for their depression. And by empirically, at the time, they weren't basing it on testing. They just said, well, let's give them a lot of methyl donors and see what happens. And they had a very high response rate for treatment-resistant depression. And so I contacted those researchers. And I said, you know, I said, I saw your paper, you know, good work. I'm doing this with, you know, not with depression, but with chronic fatigue fibro, and nobody seems to be, you know, care that much about it. I said, but here's my data. Here's what we saw. And the lead author, I think it was the lead author from Harvard, emailed back and said, oh, that's, you know, I'm really glad someone's doing that work. We see the same thing, even though we're not studying chronic fatigue or fibromyalgia. We see the same sort of benefits in the physical parameters of fatigue, pain, et cetera. what you report, you know, in your outcomes. So that was sort of at least a little bit reinforcing. And so you might wonder, you know, how long ago was this? Well, the work we were doing with the patients was anywhere from about 13 to 17 years ago. And the reporting of it and getting it out, you know, to the community was, I think, in 2012. So at this point, you know, about 12, 13 years ago. So that was, you know, that was at the very early— and then very right after that, you start to get, you know, the ability to test all these SNPs and all stuff. But I have had people ask since then, gee, it seems like you were able to do very aggressive methyl cycle treatments. So MTHFR is one part of the methyl cycle, right? So what we were doing is giving support for the MTHFR part, but also support for the rest of the methyl cycle. Because, you know, cycles in biochemistry, if you support one part, you need to support all of it. And they said, you're not having the side effects that other people see, meaning hyperirritability, tachycardia, not sleeping, headaches, other stuff. And so they would say, why Why are you not seeing those side effects and you're doing, you know, fairly aggressive support here in the methyl cycle? Well, the reason it turned out that we were not seeing those side effects, which was a sort of a happy accident at that point, and then we learned from it, was we had already been treating— remember, they'd been working with us for 1 to 5 years at this point. We had already been treating all their other underlying portions of their health. So that would include things like their digestive system health, changing their diet, getting them to move more, move the body in whatever way they And treating chronic infections, balancing out endocrine imbalances, looking if there were any toxins. All of that stuff all was being treated. So the methyl cycle treatments were on top of a really good base of treating the rest of the body, which is why we did not have you know anybody have a bad reaction to the treatment, even though it was fairly aggressive. And so what we learned from that and by other colleagues kind of going the opposite way and doing methyl cycle treatment first was if you jack up the methyl cycle and get that going and the person's really sick, they're just sick at a higher speed. And so they feel worse initially. So it's not that you can't start and work on everything, but if you're going to start when the person still has lots of other things wrong, you want to start with a lower, more kind of mellow approach to supporting the methyl cycle and then work your way up, build your way out. So anyway, that was what we discovered in the research that we finally put out in 2012. It was the first time that it was shown that there was a difference in a particular group with between the normal population and fibromyalgia chronic fatigue. And then it was also shown that it helped their scores improve as far as their CFS/FMS disease scores were able to improve. So it was really pretty interesting. And since then, of course, many years later, it becomes something that we try to look at in any chronic type of illness, whether it's those or people with post-surgical complications, post-chemotherapy complications, long COVID, or other post-viral illness, and on and on and on. All right, I'm Dr. A. 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