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MEGLATHERY MD: RCCX MODULE MAY EXPLAIN OVERLAPPING SYNDROMES

Discussion in 'General ME/CFS News' started by JaimeS, May 2, 2016.

  1. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Dear Dr Meglathery @stripey14),
    As you may know, I am a retired academic physician who advises charities on ME/CFS research and am on the board of directors here at PR. My work was in autoimmune disease but early on I got involved in hypermobility and associated systemic features. (For what it is worth I am not very convinced that there is a relation between hypermobility (or EDSIII) and ME/CFS and tenascin looks to be a very small part of the hypermobility story.)

    I have looked at your site and in particular the bit for scientists and your article draft. So far I am not clear why we should think so many different clinical problems should stem from these four associated genes. The article draft is not written in a scientific style - which basically means it is pretty hard to find the arguments.

    I appreciate your enthusiasm for initiating research into ME/CFS but I do wonder whether either you or Dr Herbst (who appears to specialise in fat disorders) are in a position to set up a viable study. I worry about that because you are asking for donations and you will be aware that PWME often are short of cash. I am sure your intentions are good but it is now so easy to ask for money over the internet that the dividing line between 'legit' and otherwise can get blurred. Would it not be wise to get positive feedback from an expert in the field before asking for donations?
     
  2. JaimeS

    JaimeS Senior Member

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    Depending on the exact funding opportunity you're referring to, it may be that these funds only apply to those who work at the NIH. These funds many be allocated to intramural studies.

    -J
     
  3. stripey14

    stripey14

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    Hello Dr. Edwards,

    Thank you for your input. I understand your concerns and recognize that this can be a vulnerable population, eager for hope, so I would like to address your concerns.

    This theory was vetted with a huge expert in the EDS field before and after I wrote the Journal Article which was written for Medical Hypothesis (which explains the less scientific format). He was encouraging but involved in working on this in his own way within his area of expertise. I was unsuccessful in connecting with people who could prove it with a sophisticated genetics labs.

    Since writing that article, many aspects of the theory have become more clear and evidence has presented itself in terms of patients sharing their personal histories with us and renowned experts contacting me and sharing the website. Right off the bat, I have received positive feedback from geneticists outside the US and since then many afflicted physicians who believe that this is correct. Two days ago, I was told by multiple people that one of the most prominent EDS experts has been sharing the theory with all of her contacts. Additionally, many known CYP21A2 carriers have also contacted me, sharing that all of the co-morbid conditions are scattered throughout their families and they are also sure I am correct, across the boards.

    My significant other is an academic leader in internal medicine and because of my theory he sees patterns in his hospitalized patients and is able to predict family histories to the amazement of many of his patients. The compelling evidence is that many sick people show evidence of the kinds of findings in people with untreated congenital adrenal hyperplasia (untreated-because treatment with cortisol in infancy changes the presentation): gender fluidity, high intellect, PCOS/hormonal issues, tendency toward being left-handed/ambi, etc. etc..

    I have found that the CAPS profile (psych profile involving sensory sensitivities, outside of the box thinking, perfectionism, etc) which can be explained by abnormal hormonal exposures in infancy (including the larger than normal amygdala found in EDS) and evidence of androgenization in women can predict MCAS and chronic psychiatric and medical illness clinically (anecdotally).

    I disagree with you on several points. The EDS population is rife with CFS/ME and the huge number of symptoms are exactly the same. Spending time on forums for all of these conditions makes it clear. Living with decompensated EDS, POTS, MCAS, CFS really makes it clear. As discussed above, decreased tenascin or tenascin insufficiency is a rare cause of EDS, but abnormal tenascin X due to TNXB mutations is rampant (as evidenced by the high rate of calcific aortic valves and vesicoureteral reflux and high percentage of people with those very recently being found to have abnormal-not deficient in quantity-tenascin and some hypermobility).

    Karen Herbst MD PhD is an internationally recognized expert in subcutaneous adipose disorders and has or will be publishing soon the high rate of hypermobility in these disorders. CFS is known to be associated with Dercum's. She sees this CAPS profile in a high number of her patients. As mentioned above, the CAPS profile is one of the markers I have found.

    Further, everything on the list can be explained by these mutations. TNXB: varying degrees of hypermobility, high TGF beta likely explaining the high rate of endometriosis, fibrotic issues,likely contributes to dysautonomia due to lax vessels, musculoskeletal injuries due to tissue weakness in some; CYP21A2: stress vulnerability as this codes for the key enzyme in the acute stress response, CAPS, see pathophysio diagrams for POTS, MCAS, Adrenal fatigue, raised ICP, hormonal issues, exaggerated stress response before sick, crashing and body and brain inflammation via high CRH afterward 21 hydroxylase overwhelmed.

    The acute stress response is very much tied to inflammatory conditions-look at what people with PTSD get (very similar to us). C4: associated with MS, autoimmune diseases, now schizophrenia, etc. It has been shown that these genes travel together very frequently in the literature, causing conditions like EDS and CAH to co-occur at a much higher rate than by chance. C4 has been shown to run with CYP21A2 at a high rate as well.

    The donations to the RCCX Project are for research looking into the RCCX module's role in chronic illness, not specifically for Karen and I. If someone came along and had the facilities to do a large scale study on the RCCX, the funds would go there (for example someone like Ron Davis PhD). Karen and I have unique expertise to look at the clinical aspects of CYP21A2, including CAPS and the hormonal derangements and I believe we would be a very valuable asset to any study looking at this.

    We may even have to hire a top RCCX genetics expert for our samples if the University of AZ lab is inadequate and we are testing the lab right now with CAPS patients and will have our lab fully vetted before we use our donations to pay for the testing. Karen is paid by the university to do research and will not use the donations for any of her work. I am volunteering my time at significant cost to my personal life and health because I so strongly believe in this cause. If our genetics lab is inadequate and we don't have the money to hire an expert, we will return the funds we receive, minus the lawyer fee for setting up the nonprofit.

    I think that the evidence and the website speaks for itself. I am not able to put too much effort into arguing these points (due to my own health), which is why I put it all out on the website and did not take the conventional approach which would have involved writing and rewriting this. I surely would have ended up disabled, as my level of illness directly correlates with my level of stress (goes with the theory).

    It took a lot of thought before I released the website. The last thing I wanted to do was to become a public figure and I already have a 6 month waiting list for my practice which is not directed toward treating chronic illness. I had no intention of being involved in the research effort when I first posted the website for a test run (which involved 13000 views in a week and an outpouring of support). With this response from the EDS community and beyond and Karen contacting me, it was clear that we had the skills to greatly contribute to this effort. It's a grass roots effort. If I am right, looking at the RCCX could save years in studies trying to work backwards from downstream derangements, and there can be some directed treatments developed for us, rather than outrageously expensive immunological drugs which I believe try to block downstream issues.

    As I know that the CAPS psych profile (smart, good at seeing patterns as part of it) is high in this community, I know that people in this community will take a look at the theory and decide for themselves whether they or their family medical histories could be explained by mutations of these genes co-segregating. I f they believe in it, they know where to find us (above).

    I'm here for questions, but I'm heading into my work week and need some time to decompress before then :)
     
    Last edited by a moderator: May 15, 2016
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  4. leela

    leela Slow But Hopeful

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    It's nice to see @stripey14 here, thank you for joining the conversation.

    In answer to the original question @JaimeS asked, I'll add that I do know someone who is her patient, and she has had good things to say.
     
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  5. Valentijn

    Valentijn Senior Member

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    To be clear - you're saying that a specific psychological profile predicts ME/CFS? Can you direct us to the peer-reviewed published research supporting that rather extraordinary claim? (Other that the documents "published" as "The Journal Article" on your own site).

    This would suggest that you are badly misunderstanding the symptoms and existing research of one or both diseases.

    Maybe you should spend more time on this one reading about the experience of ME before making such assumptions.

    Do you have a reputable citation for this? It's again an extraordinary claim, and I've never heard of research or even an anecdotal patient report of such a thing. And FYI, this is an ME forum. Many find the term "CFS" to be inaccurate and insulting, especially when used without "ME/" in front of it.

    I've seen "genetic" studies run by psychiatrists before, and can't say I've found them to be at all impressive. And of the many ways to spend my rather limited cash, a study attempting to integrate psych profiles into a biological disease, or conflate numerous biological diseases with each other is pretty low on my list. It's been done before, ad naseum, and the results have never been of any use and often even resulted in harm.
     
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  6. Valentijn

    Valentijn Senior Member

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    For those who are wondering, the "CAPS" the doctor is referring to above is her hypothetical "CAH1 Associated Psychiatric Spectrum Disorder". She believes the condition is responsive to deep breathing, exercise, stress management, improving social skills, cognitive behavioral therapies, acceptance and commitment therapy, trauma therapy, mood stabilizers, anti-psychotics, and a few other more sensible treatments.
     
    Last edited: May 16, 2016
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  7. stripey14

    stripey14

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    Hello, I was going to let the previous comments stay without discussion as I expect that the audience here will go and look for themselves and it is late on a night before work. But this second post grossly distorts what I say on the website and I won't let it stand as it may deter people from taking a look and may prejudice people against the theory and against me as a physician.

    CAH1 stands for congenital adrenal hyperplasia heterozygosity. CAPS is a psychological profile similar to the HSP (highly sensitive person) profile which I believe results from the hormonal derangements secondary to being a carrier for a mutation in the CYP21A2 gene which codes for 21 hydroxylase, the enzyme responsible for converting for 17 hydroxyprogesterone to cortisol. This is the primary enzyme for the acute stress response. We know that carriers for this mutation over respond to stress . My hypothesis is that with prolonged or extreme acute stress, the ability for this enzyme to produce cortisol is overwhelmed and subsequently high CRH turns on inflammatory cascades including mast cell activation syndrome. At the same time, cholesterol, progesterone derivatives and androgens can build up.

    The purpose of my website is to get a novel idea out and not to make treatment recommendations. I talk about possibilities for drug development of the theory is correct and I also discuss the importance of avoiding a prolonged or severe acute stress response so that 21hydroxylase levels remain adequate for the level of stress. I discuss CRH blockers, progesterone blockers, cortisol replacement, salt, hydration, Berberine, MTHFR correction, mast cell treatment and inflammation treatment as well. Therapies to decrease the acute stress response, including therapy, exercise and mindfulness are also discussed as are treating comorbid psych issues from brain inflammation, including severe mood swings and psychosis.

    I know that this community is sensitive about the recent Pace study and I have this illness so I am not here to say that that is the sole treatment. I'm invalidated by that idea as well!

    I am going to take a step back from this forum as I have patients for the next couple of days in clinic, and I believe that the people who would like to entertain some new ideas will check out the website. That's all I can do. I need to do what is effective. I believe in this theory and so do many other people. Time will tell. I'm not asking anyone here for help or money. I'm just sharing something I spent years putting together. Right or wrong, it's out there for you to consider. That's it. Goodnight.
     
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  8. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Dear Dr Meglathery,
    I am afraid that the only way that the website 'speaks for itself' is to suggest that the theory is unclear and the evidence at best anecdotal or controversial. Anything and everything can seem to fit a theory if it is vague enough. Getting people to send things in on the internet will just gather together the things that seem to fit. Problems like this need to be addressed on a proper epidemiological basis.

    The comment on rituximab does not help your case. What PWME need is good research, not people committed to this theory or that before they start.
     
  9. Valentijn

    Valentijn Senior Member

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    A stress model for ME/CFS has been proposed many times before, and generally fails to explain most symptoms and biological research into ME/CFS. I really don't see how your hypothesis accounts for these symptoms or research findings, and the writing on your site is not clear or organized enough to find the answers to these questions.

    Like Dr. Edwards, I also find it odd that you are so dismissive of a trialed effective therapy, while promoting a very unlikely hypothesis. Even if you believe that the likely aberrant B cells are somehow a downstream effect of a generic stress response, I don't see how such a belief could be reasonably explained. There is a similar problem with your hypothesis in light of much other ME research, such as the two-day CPET documenting PEM. How could a stress model conceivably lead into such symptoms?

    Your hypothesis and research seem to exist in a bit of a vacuum. The context of specific and important symptoms, the context of research into biological abnormalities, and the context of research into biological treatments seems to be completely omitted from your hypothesis. It feels like you're creating a model out of thin air, with no awareness or accounting of what is already pretty well known, or what is already disproven, and ending up with a contradictory and unlikely hypothesis as a result.
     
  10. barbc56

    barbc56 Senior Member

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    Dr. Meglathery is a holistic mental health clinician, a term I'd never heard of before, but explains a lot about her approach. Especially the way her theory is presented in a less than scientific manner and seemingly dismissive attitude towards a potential treatment that uses a medication.

    The implication is an overemphasis of the mind body connection. By overemphasis I mean giving too much credit to the psychological component of a physical illness, not that it doesn’t exist. We've seen too many times how ineffectual and harmful treatments such as PACE, mind over matter therapies such as the Lightning Process develop from this school of thought.

    I think this is important when considering the validity of this theory. Too many red flags for my taste.
     
    Last edited: May 17, 2016
  11. nandixon

    nandixon Senior Member

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    It's important to be aware that (1) various immune cells, including B-cells, have glucocorticoid (and mineralcorticoid) receptors on their cell surfaces, and (2) that immune cells are involved in a large number of biochemical signaling processes (including crosstalk with each other) that can be related to these receptors.

    Given these receptors, a potential connection between stress and cortisol, for example, and immunological-related effects is obvious.

    In the case of the B-cell depleting drug rituximab, it's just as likely at this point that any beneficial effects of that drug for ME/CFS are due to interference with some signaling process that involves one or more of the immune cells, as opposed to correction of an autoimmune problem (although both problems may coexist). And that signaling process could obviously have a glucocorticoid/mineralcorticoid aspect to it.

    So I think that Dr. Meglathery's (@stripey14) hypothesis, as it involves the CYP21A2 gene, which codes for an enzyme (21-hydroxylase) critically involved in the production of both gluco- and mineralcorticoids, is well worth exploring and I wish her the best of luck.
     
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  12. JaimeS

    JaimeS Senior Member

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    Yes, to be fair, this was one of the first things I was tested for: atypical presentation of 21-hydroxylase deficiency. By a local endo and, at the time, I remember thinking that it was a remarkably skillful shot in the dark.

    However, I tested negative for errors 21-OHase metabolism on every test they had.

    -J
     
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  13. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I agree that cortisol receptors on B cells may be relevant. However, the time course of response to rituximab pretty much rules out an effect on B cell signalling per se. Remember that there was no effect until 6 months after treatment. Shifting corticoid signalling has an effect within hours. And I cannot quite get my head around why getting rid of B cells should be a way to deal with a genetic steroid metabolism shift. As far as we know the corticoid receptors on B cells are just there to modulate their control of antibody production. It might be autoantibody but we have discussed that before.

    Dr Meglathery seems rather underimpressed with rituximab anyway!
     
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  14. nandixon

    nandixon Senior Member

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    A scenario that I think works, and that I was envisioning, is that the B-cell signaling has caused a change in another immune cell, e.g., a T-cell of some variety. That change might have to do with a change in gene expression that has become effectively permanent for the life of the cell (e.g., an epigenetic change to a T-cell).

    Under that scenario, the 6-month period isn't relating to the gradual dying out of autoantibody-producing plasma cells, but rather to the gradual dying out of the affected T-cells (for example). This scenario also appears consistent with why cyclophosphamide appears to work more quickly than rituximab in ME/CFS.
     
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  15. lansbergen

    lansbergen Senior Member

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  16. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Yes, this idea of taking away B cells quietening down T cells has been very popular with immunologists and I cannot say it is impossible. However, nobody has ever found anything wrong with T cells in autoimmune disease, that might provide an effector mechanism. Most immunologists are brain washed into thinking there are autoreactive T cells but nobody ever found one as far as I can see (except maybe in AIRE and a few exceptional situations). We can see the CRP falling in parallel with autoantibodies in RA and it would be a bit of a coincidence if there was a similar lag period in ME for a completely different reason. Cyclophosphamide is expected to work early because it kills short lived plasma cells directly.
     
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  17. wastwater

    wastwater Senior Member

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    I have a rare eye disorder Axenfeld riegers syndrome and about 10 percent of people with it seem to have some kind of immune dysfunction speculated T cell problem that resembles fibro ME/cfs it may actually be part of another genetic disorder. I don't have any of the features of EDS I don't think,but one gene that is mentioned is COL4A1 (very rare)
    FOXC1 being the other of interest
     
    Last edited: May 19, 2016
  18. Jenny TipsforME

    Jenny TipsforME Senior Member

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    My main reason for commenting is in terms of personality typing. I have a natural curiosity about this (psychology graduate) but it can be dangerous. Sampling would need to be very good to test this as obviously behaviour is effected by personality. I noticed a high proportion of pwme online said that they are INFJ on myers Brigg (or with just 1 letter difference). This is the rarest type about 1% from memory. This seems remarkable until you read that INFJ/P really like discussing personality on Internet forums! We are the ones who want to talk about this, ESTP pwme likely find it very boring and likely haven't bothered to do the test. Similarly YUPPIE flu came about as a stereotype more because you had to be quite confident and educated to get as far as a CFS diagnosis. This didn't accurately reflect who was ill. In fact isn't there opposite epidemiology that shows low socio-economic factors are risks for ME/CFS?

    Having said that I do fit the HSP mold and have a number of the issues mentioned.

    I'm finding this conversation interesting as it coincides with trying to interpret my 23andme data. I'm a bit confused about @stripey14 comments on the 23andme and CYP21A2. I do seem to have some results for that, is it just not complete? The only 'bad' one Promethease says it is miscalled by 23andme. Is the idea that more thorough genome testing is required?

    I wanted to know if I have EDS (have POTS and loose ligament issues on my knees). I don't have any genetic risk for EDS.
     
    Last edited: May 19, 2016
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  19. Snowdrop

    Snowdrop Rebel without a biscuit

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    The problem with typing/myers-briggs or anything of the sort is that this disease changes you over time.
    I have only vague glimmerings of what kind of person I might have been (and here I mean personality not function) if I had never been sick.
    There is a large youtube presence on ME/cfs people as sensitives as if this is a personality type rather than a biological reality due to physical systems malfunctioning. All of these things are not binary but exist along a continuum which adds to less precision in determining similarity/dissimilarity.

    I don't see how bringing personality into the discussion of ME/cfs contributes anything.
     
  20. Jenny TipsforME

    Jenny TipsforME Senior Member

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    @Snowdrop yes that was another aspect I thought of mentioning. I didn't do Myers Briggs before ME so can't say for sure (though I am still the same type on Eysenck PI pre ME I was more neurotic and less introverted).

    Sensory overload issues might make us appear more introverted. Dysautonomia could make us seem more anxious. There may also be trauma at the level of PTSD from difficult repercussions from ME.

    I'm assuming with @stripey14 's theory she is saying that the personality aspect is biological, due to mutation. I hear the idea that it can be diagnostically useful (as outward sign of genetic mutation) but disagree with going on that tack.

    The association between SNPs and aspects of personality has surprised me with my own dna (with caveat that it's very easy to read too much into this). These are things people have remarked about me, not just one of many traits. I can see that an expressed SNP could BOTH lead to disease and a particular personality style.
     
    Last edited: May 19, 2016
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