Discussion in 'General ME/CFS Discussion' started by debored13, Oct 6, 2018.
i found this theory, which is very complicated, and I can barely begin to understand, that seeks to explain underlying genetic causes for CFS and overlapping illnesses
@Learner1 @Hip @pattismith @Iritu1021 I don't know if you guys have all seen this
Just with a quick read through the summary, some parts confuse me. I don't have hypermobility and I seem to do well in response to supplemental progesterone, while this theory supposes high progesterone being responsible for many symptoms. Maybe it's something I'll look at stopping despite that though.
RCCX Theory: Summary
In Brief: (Much more detail to follow)
Co-inherited gene mutations of the RCCX module may explain presence of clusters of genetic illness in families and individuals involving hypermobility/fibosis (TNXB gene), chronic medical illness (CYP21A2 gene, i.e. EDS-HT, CFS/ME, FM, POTS, MCAS, etc.), psychiatric illness (CYP21A2 gene) and autoimmune diseases (C4 gene).
CYP21A2 gene mutations could confer a stress vulnerability for the development of chronic medical illness (EDS-HT, CFS/ME, FM, POTS, MCAS, etc.) via "21hydroxylase overwhelm" and via PTSD-wiring from CAPS (CYP21A2 Mutation Associated Neuropsychiatric Spectrum) plus negative events.
CYP21A2 gene mutations create a hormone milieu which could affect the developing brain, making it a "brain wired for danger" by age 5, also known as CAPS (CYP21A2 Mutation Associated Psychiatric Spectrum). CAPS likely predisposes to 4/5 of the major psychiatric illnesses (anxiety disorders, mood disorders, attentional disorders, autism spectrum).
Both "21hydroxylase overwhelm" and PTSD wiring associated with CAPS could turn cause stress-induced mitochondrial shutdown
Yes, I have investigated Meglathery and her RCCX theory. She seems to be very devoted to it, having put a lot of effort into it.
I think I fall into the skeptical category. I don't know what myths she is talking about and tend to prefer things that can be identified and measured to verify any theory, which seems impossible from what I've read with this one.
I don't know if the theory is correct or not, but the issues I have are:
She is a psychiatrist and I don't believe in what psychiatrists do, having learned that most mental illness is due to food allergies, leaky gut, nutrient deficiencies, infections, inflammation, toxicity, and very occasionally and less commonly some awful SNP or SNPs.
She is not providing rs numbers that anyone can check, either on 23andme, WES, etc. She just goes on and on and on about these genes, which everyone has. Which SNPs are they and what role does each one have in this? How do you know if they are doing it?
Genes can express differently based on environmental factors and how other genes are expressing themselves. Just because one has a pathological SNP, in many cases, it's not expressed until the right environmental factors are there.
Sure they can create many of the symptoms she refers to, but I have found it's more productive to look at what's going on biochemically or perhaps with physics, and to try to "normalize" whatever is out of whack, using a systems point of view, with a combination of supplements, pharmaceuticals, hormones, stress reduction, and techniques that affect the physics (acupuncture, trigger points, and other modalities).
If she is correct, this may apply to some of us, but likely not to most of us, as she herself admits.
Then there is the question, if one can figure out that all this applies, what does one do about it? After reading and reading and reading, I don't see a thoughtful, comprehensive, treatment approach that will get anyone anywhere. Mindfulness is wonderful, but what she is describing is going to take more than mindfulness to fix.
ME/CFS is indeed a complex disease. The scientists believe causes are heterogeneous and that there are subsets. There likely is a subset with some of the qualities Meglathery describes. The scientists have already been finding SNPs that seem to cluster in ME/CFS patients, none of which seem to be the same as those on Meglathery's list.
My own journey has brought me a long way with personalized medicine. It's been by necessity, because there just isn't enough research out there to nail the perfect ME/CFS theory and I don't have years to wait for perfection. I've also found that I have some SNPs (HFE, Factor 2, SOD2, and many more) and environmental factors (carboplatin and paclitaxel) likely not shared by others and on top of all the usual ME/CFS factors that have confounded my situation, so that unique treatment components must be personalized. Each one of us will have unique factors as well.
So, while theories are interesting, the way to get well is to normalize the body's biochemistry and physics. Theories can help us, but there is no substitute for high quality lab work and other testing and a prioritized, personalized, systematic treatment plan, which unfortunately is no easy task.
Thanks for sharing @debored13 - I appreciate your continued quest to bring in interesting ideas and move the dialog along.
I agree with all of these things. But I'm trying to do a charitable read of it. As far as the first point I bolded, I'm sure you've noticed that I'm incredibly skeptical of psychiatry as a discipline already. But if she is talking about complex biological underpinnings to illnesses like this to this extent, she is already better than 99% of psychiatrists.
As far as the second point, the person who originally showed me this theory assured me that 23andme cannot test for these mutations, because of the location?? or something.. but this isn't surprising to me as consumer grade genetic testing seems like a lot of hype and it can't test for many things in the genome.
Mostly yeah I don't see much workable and all of it doesn't apply to me but there are some interesting things about hormones.
And yes, focusing on genetics isn't really helpful for the majority of us given that genetics is in its infancy and doesn't generally provide workable things on a patient/consumer level, but it might yield clues, I don't know
Well, I think it's useful to consider complex theories as something Interesting can pop up that leads to a breakthrough.
And I dont underestimate genetics at all. I think that some of us got dealt a better hand in the genetics department than others, and finding pathological SNPs and dealing with them effectively can dramatically change our outcomes.
The trouble is, 23andme is missing a lot of genes that would be useful to know about, interpreting a single gene in isolation is problematic, and it's usually a combination of multiple genes and environmental factors causing disease.
So, it's useful to keep abreast of the theories and science and hope something will click and lead us to a cure...
I had a quick look. I can't say I understand it, but the following extract from this page on Dr Meglathery's site seems to summarize some of the theory:
CYP21A2 is the gene that manufactures the enzyme 21-hydroxylase. This 21-hydroxylase enzyme converts 17-hydroxyprogesterone into cortisol and aldosterone. Dr Sharon Meglathery says 21-hydroxylase is the most important enzyme in the acute stress response.
Then this page on the site says:
So this seems to be saying that these CYP21A2 mutations are theorized to lead to a pro-inflammatory tendencies in an individual, which may be risk factors for certain chronic diseases.
I could not find any mention of which CYP21A2 mutations might be involved. If we knew these, we could perform a survey on ME/CFS patients here, as you can see your CYP21A2 mutations on 23andme here.
I think the reason chronic stress (produced by events such as divorce, bereavement, etc) is a known risk factor for developing ME/CFS is because this stress and the elevated cortisol it produces inhibits the antiviral immune response. Then if you are unlucky enough to catch an ME/CFS-associated virus (like enterovirus or herpesvirus) during a time of such chronic stress, the acute viral infection will meet a weakened immune system, and this may allow the virus to insinuate itself more deeply into tissue compartments (such as the brain) which it may not have been able to enter if it had met a strong immune response when you first caught the virus.
Of course it could be that any CYP21A2 mutation you may have will make you more vulnerable to life stressors, so this could also be a factor in stressors weakening your antiviral immune response.
This also relates to Dr John Chia's discovery that corticosteroid drugs like prednisone incorrectly prescribed during acute viral infection are associated wtih a high risk of developing ME/CFS from that virus. Dr Chia says he sees hundreds of ME/CFS patients whose ME/CFS was apparently caused by a doctor inadvertently prescribing steroids during the time the patient had an acute viral infection.
In this corticosteroid + acute infection scenario, the corticosteroid drug plays the same role as chronic stress. Chronic stress causes the natural release of cortisol, whereas taking corticosteroid drugs pharmacologically simulates the natural release of cortisol.
I think Dr Chia's discovery corroborates the previously discovered chronic stress connection to ME/CFS, and provides evidence for the theory that chronic stress may allow an ME/CFS-associated virus to insinuate itself more deeply into the body during the acute infection.
I wrote about the RCCX theory in a blog for Health Rising. I think she is definitely on to something important and her background as a psychiatrist is far less relevant than her experience as a fellow patient, in my opinion.
You can’t test for these mutations yet with the current available testing but hopefully that will change. I explain why in the blog.
Glad that you were able to understand the essence of the theory, Ema! My brain is struggling!
There is a fascinating video podcast and its transcript on the RCCX gene cluster here, in which Michael McEvoy explains:
Seems that in order to understand RCCX genetics, you have understand copy number variation (CNV), which is where parts of the human genome get duplicated and repeated, and the number of repeats varies between one individual and the next.
The podcast says:
We are used to thinking of single nucleotide polymorphism (SNP) mutations (which 23andme details) as the main factor that differentiates one person from the next, and the primary genomic influence on disease.
But it seems that copy number variation (CNV) is also associated with chronic disease. So your SNPs do not by themselves give the full picture.
I like this bit from the podcast, about intellect and RCCX:
This part of the podcast explains why you cannot get data about your RCCX gene region from 23andme:
And it's interesting that human endogenous retroviruses (HERVs) are also found in the RCCX gene cluster, and that these endogenous retroviruses may play a protective role:
It was not easy! I went through three drafts of that paper (the longest was nearly 8 pages single spaced!) before we got to the final one that Dr Meglathery and I both liked.
Michael McEvoy has written some great stuff on RCCX but he has gone off in some directions of his own, as one does, after learning about this complex from Dr Meglathery. She doesn’t support all of the conclusions he draws (but I’ll be darned if I could tell you which ones those are specifically at this point).
It’s all just a theory still but one well worth pursuing, IMO.
What's strange to me is that she completely omits the role of thyroid hormone in this. As a psychiatrist, she should know that it's an effective treatment that's shared both in people with bipolarity and CFS/POTS - three conditions that she correctly linked together. Although I guess the new generation of psychiatrists are no longer using thyroid hormone after the big pharma intervened with more expensive and less effective drugs.
Also, she talks about copper and berberine as something she tried with mixed results and attributes their effect to steroid synthesis. However, berberine is a 5HT1A receptor agonist (similar to T3) and copper is involved in dopamine synthesis (which explains why she initially felt better on it and then felt worse - similar to what happens for most of us when we take stimulants).
While I'm wholly sympathetic to this, I don't think it's necessarily widely known that thyroid can help in CFS, for whatever reasons. Even the people who got benefit tended to have a rocky time and have to find very specific protocols that they just as easily could have given up if not informed.
Naviaux and Davis and Fluge and Mella, all talk about metabolism a lot but never mention thyroid. I was kind of curious about why that is, if hypometabolism is clearly shown and thyroid is the main regulator of metabolic rate, but as I try and complexify my thinking, I see a number of different feedback loops and possible traps in metabolism that could be not always alleviated by thyroid (although i certainly hope they are, hehe).
Also, as far as I can tell, most psychiatrists don't really know about metabolism at all. The ones i have had just know basic stuff about monoamines for the most part I think
anyway, i agree with @Hip that the part in RCCX theory about predispositions and personality, negative traits and gifts, was interesting. The biopsychosocial people and the backlash to that psychosomatic model of CFS has probably made it less in vogue to talk about stress and trauma, even though those are complex physiological phenomena, not just in your head, and predispositions to these could be important in looking for etiology, genes, etc.
I know pre-illness I was "healthy" but not that healthy... Obviously I can't even compare the mental illness and stress I had then to the awful level of impairment I have now, but I certainly was not good at handling stress, I'll put it that way. It wasn't "just" stress that caused my illness but I wonder about the genetic components to handling stress.
I had an OCD diagnosis as well as anxiety and adhd. I had not handled the stress of school well at all and at some point right after I initially got sick, stims started to just add to that stress. I was not "type a" in terms of being very organized, but I was very idealistic and ambitious I think, in a way that sometimes caused me stress and still causes stress because I get further and further from being able to do any of what I wanted now
T3 clearly does something for CFS - and you've experienced it for yourself. But T3 is not a solution on its own.
I'm now pretty much back up and running back at my pre-crash level thanks to a well-calibrated combo of lithium orotate and levothyroxine (took a lot of faith into what I was doing to get to this point). While this may not work for everyone, I doubt that I'm a total outlier as I was diagnosed with a "classic CFS" and POTS by some very respectable specialists in those conditions (who either did nothing for me but waste my time or made me feel a lot worse). Also, mine is not some accidental recovery - if I stop what I'm taking I begin to slide back right to where I was.
The treatment I use is the classic "old school" psychiatry treatment with the only exception that I use lithium orotate instead of lithium carbonate. Lithium orotate is much more bioavailable for the brain and doesn't require toxic doses. I no longer use any exogenous T3 because I've realized that given the specifics of my CNS, it destabilizes my neurons, especially in higher dose or with prolonged use, or when combined with other stimulating drugs.
In addition, I now understand how to regulate the conversion (again lots of trial and error there - see "Peripheral Deiodination Table" I've compiled). It is much better to allow the cells do the work at their own pace than to bombard them with external T3 (which when used this way is less of a hormone and more of a stimulant).
Lithium plays a huge part in my CNS T4 conversion. I need enough levothyroxine to be able to tolerate lithium. If I were to use either one of these drugs without the other, this method wouldn't work.
Everybody is chasing something that will make them better the same day. The reality of treating CNS disorders is that it doesn't work like that. I have benefited hugely when I began reading more about psychiatry than about CFS - and the message I derived from there is that it takes time, patience and the willingness to tolerate initial side effects while the body re-adjusts before one can get better.
Complex theories may be interesting but treatments that work is what we should really care about.
Well at this point I have to focus on something that can help me even get out of bed and help with the overwhelming fatigue and exercise intolerance, before I treat mental symptoms that may arise. I'm at such a severely wrecked level physically that I need 2 be able to deal with this, and I'm not sure thyroid will, maybe it will once I find the right dosing method, etc. I mean I hope it will but I've gotten my hopes up for so many things that I try and unconditionally kill any hope I have before it poisons me. I'm already in the very experimental realm in that even if this used to be a simple treatment it's not really something a doctor that I have can help me with. sometimes that makes things harder and take longer.
I agree with keeping things simple but a lot of this ends up not being simple. i've been understanding some of the theories enough to try fairly straightforward actionable things to treat various symptoms recently.
I did have a reaction to thyroid that was initially positive enough that I'm convinced it's "the thing" to an extent, but it's so tricky. And even if I treat it, i'm not sure that it will entirely treat my CFS, there are patients who are on thyroid replacement and still sick. Metabolism seems very complicated, and mine is severely broken, albeit with totally normal blood levels of thyroid.
I have entirely normal serum levels of thyroid too and I'm pretty sure that they do not correlate with my brain levels. And I had the same issue as you did when I used a similar method to what you used, and as you may remember I predicted that it will stop working for you back when you were still feeling excited about it.
Anyway, I'm not here to change people's minds. I've made my experience and conclusions available to those who are open to it - the rest is not up to me.
Yes that's the impression I got, that Michael McEvoy is perhaps extrapolating or embellishing the theory with his own creative hunches and ideas. But I did find the transcript of his podcast helped with understanding the RCCX theory. And your article too.
Another article where Michael McEvoy explains Sharon Meglathery's theory:
RCCX: A LINK TO COMPLEX ILLNESS & WHY ITS IMPORTANT
Yes, the backlash against the psychosomatic/biopsychosocial model of ME/CFS was, and is, necessary, because this model resulted in much of the medical profession viewing ME/CFS as a purely "all in the mind" condition, which then led to inappropriate psychological treatment, and sometimes abuse of especially young ME/CFS patients.
But I like Dr Sharon Meglathery's approach, and I much appreciate it when a psychologist brings in biology to the picture, and tries to understand personality characteristics in terms of what goes on in the physical brain and body.
Yes I was the same. Even when healthy I never liked social discord, because I found it mentally stressful. Of course that feeling of stress arising from social discord is greatly amplified now that I have ME/CFS (the sensitivity to stress and emotional overload are established symptoms of ME/CFS); but to some extent this was always part of my personality.
She's a psychiatrist, not a psychologist.
Also, there's a huge difference between the terms "psychiatric" vs "psychosomatic". Jay Goldstein tried to rebrand "psychosomatic" into "neurosomatic" - a term that I think perfectly captures the nature of the disease as he saw it ("physical symptoms caused by limbic system dysfunction").
The distinction between neurologic and psychiatric illness is quite arbitrary IMO. For example, patients with Parkinson's disease have low dopamine levels but it's considered a neurologic condition. Why is then a depressed patient with low dopamine levels considered a psychiatric condition? I think the distinction is purely historical and emerged back in the days before it was discovered that psychiatric illness is a disease of the brain, not a disease of the mind.
If the top scientists in psychiatry or brain research began to really look at CFS closely, I think we'd be much further along in this than where we are now. Therefore, IMO we have not done ourselves any favors by drawing up the arbitrary wall between CFS and psychiatry.
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