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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. JaimeS

    JaimeS Senior Member

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  2. Valentijn

    Valentijn The Diabolic Logic

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    Nope. Looks like they have a theory. Just like everyone else :rolleyes:
     
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  3. Scarecrow

    Scarecrow Annie Gsampel

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    @JaimeS the short answer to your question is 'no' but that site is certainly intriguing. It seems to bring together every hypothesis about ME/CFS (and divers other conditions) that you've ever heard of into one. My brain is currently reeling.
     
  4. JaimeS

    JaimeS Senior Member

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    @Scarecrow ,

    It seems to tie endothelial damage to everything -- i.e. the 'it's all a collagen disorder' theory. Maybe it hasn't been codified anywhere, but the connection between hypermobility and autoimmune disorders has certainly been observed and commented on by many.

    Basically, I was wondering if they were legit. They do seem to be on the surface, but I figured I'd better ask about others' experiences with them, if any...,

    -J
     
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  5. duncan

    duncan Senior Member

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    Only one acknowledged known pathogen listed that I saw: Lyme. Wonder why?

    Of course, Borrelia has been known to infect endothelial cells, but I suspect that's not why.
     
  6. Scarecrow

    Scarecrow Annie Gsampel

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    As I was reading the site, in the back of I mind I was wondering if it was a particularly elaborate scam. There were definitely familial elements that I identified with but not incredibly strongly. It's so detailed that some of it is bound to resonate, right, even if most of it doesn't? Or it could be resonating because she really is on to something.

    The researcher she's teamed up with certainly looks to be genuine:

    http://www.ncbi.nlm.nih.gov/pubmed/?term=Herbst KL[Author]&cauthor=true&cauthor_uid=22301856

    All in all, I'd say legit fwiw.
     
  7. JaimeS

    JaimeS Senior Member

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    Thanks, everyone!
     
  8. ukxmrv

    ukxmrv Senior Member

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    I've come across Dr Karen Herbst in relation to another condition I have Lipdema. The woman who have been to see her (on similar forums to PR) seem to think highly of her
     
  9. barbc56

    barbc56 Senior Member

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    Looks interesting but haven't had a chance to read it all.

    I'm wondering about RLS being under psychiatric conditions. But I'm not sure what she's saying as each time I read it I think she's saying something different.

    Excuse my foggy brain!
     
  10. aaron_c

    aaron_c Senior Member

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    I had a physical therapist tell me that this is what was causing my ME/CFS...

    Can someone who knows more about genetics tell me if the bold part of the following statement is true?

    The RCCX module is the only place in the human genome where two genes have been shown to travel together frequently, causing two disorders to be present in the same person at a MUCH HIGHER RATE in populations of people with these genes. Specifically, studies have shown TNXB and CYP21A2 to run together frequently, as well as to suggest C4 runs with CYP21A2 frequently as well.
    I thought that when genetic recombination occurs in meiosis, there are a whole lot of pairs of genes that are more likely to stick together than other pairs of genes. Is she talking about something different?
     
  11. Thinktank

    Thinktank Senior Member

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    I find such theories interesting and will take my time to read it. Although i don't know anything about genetics really.

    23andme shows i have a heterozygous mutation on CYP1a2, and labtesting always shows C4 is low.
    Does that mean anything?
     
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  12. Little Bluestem

    Little Bluestem Senescent on the Illinois Prairie ❀❤✿Ƹ̵̡Ӝ̵̨̄Ʒ✿❤❀

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    Maybe what she means is: The RCCX module is the only place in the human genome where two {disease causing} genes have been shown to travel together frequently, causing two disorders to be present in the same person at a MUCH HIGHER RATE in populations of people with these genes.
     
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  13. JaimeS

    JaimeS Senior Member

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    Took a closer look at the site today and I do think they're likely on to something, though it's going to take quite some time to get something like that off the ground -- and their research base is so darned broad that I'm not sure they can make anything of it.

    They do need to hire a writer or editor. There's too much information per page, and I don't think I say that just as someone with profound brain fog. The site could do with some reorganization.

    But in any case, after verifying with you guys that these people weren't pinging anybody, there's a piece on #MEAction about them now. Not set up as 'featured' because generally no one asking for money is set up as featured (with rare exceptions).

    -J
     
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  14. stripey14

    stripey14

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    Hi All, I am Sharon Meglathery MD and this is about my theory. I just saw this post last night when the analytics for the website pointed me in the direction of Phoenix Rising. I was planning to connect here anyway when I had a moment :). I have followed the forums here for years.

    Karen Herbst MD PhD and I are trying to get to the bottom of this. She contacted me 8 hours after I test-released the website, saying I was right and wanting to work with me. As I said in the website, my health is tenuous and I did the best I could with the website. I tried to write clearly and at a 6 grade level (that's what they say in med school) and I had an editor friend go over it before I published. She has no science or chronic illness background and she assured me that it got the main points across as simply as I could. I am not operating with all of my cylinders firing, especially with the stress of trying to get this theory investigated, so I just got it out there. I had a moral and ethical obligation to get the theory out as far as I am concerned and it had to happen quickly for my own health.

    I attempted to give the theory to many researchers before releasing the website, but I couldn't get an audience with any of them. I wrote saying I am an MD with chronic illness and wanted to share what I figured out with no strings attached. No response until last week when Ronald Davis PhD sent me a personal letter saying he had found a letter I sent to him in November and asking me to send the theory. I sent a packet and plan to follow up soon. If he's not interested, no harm no foul. If he is, then the RCCX Theory will certainly survive to be tested.

    I know this will be an uphill climb but I have received a great deal of clinical confirmation that this theory is correct (the most compelling from known CYP21A2 carriers with everything I describe). Right now we can only test for only a few severe CYP21A2 mutations as the vast majority of mutations are not characterized (which is what Karen and I need to do). Even whole exome sequencing may not get at this because the RCCX is riddled with pseudogenes, retrotransposons etc and mutates often. Knowing that one has irregularities in this region is not enough to be able to say anything about the person clinically.

    Karen and I really have our work cut out for us. We may need to hire a very very sophisticated genetics lab. We are trying to see if ours is adequate first. Our plan is to do very sophisticated endocrine testing and challenges, psychological testing (lloking for the CAPS profile) and correlate with what is seen in CYP21A2 analysis. Once we figure out the clinical correlations, we can then get genetic info alone from afar. Of course, we will be looking at TNXB and hopefully C4 as well. The difference between this theory and the others is that CYP21A2 may be the ACTUAL stress vulnerability gene for chronic illness, rather than a gene associated with downstream effects.

    The fact that most people with chronic illness have evidence of increased androgen exposure in utero in my clinical experience and being borne out on my FB pages (women with longer ring fingers than index fingers and the CAPS psychological profile-also presumed due to androgen and stress hormone exposure in infancy) provides support for this theory. It is not at all a collagen/endothelium theory which I am sure was noted when Jaime took another look. I hope all of that is clear. I have set up a FB page for updates: rccx and chronic illness, a discussion group on FB: rccx and chronic illness discussion.

    Thank you for posting JaimeS!
     
    Last edited by a moderator: May 15, 2016
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  15. JaimeS

    JaimeS Senior Member

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    @stripey14 -- welcome to the forums! As a researcher, the best way to engage with the community is to post occasionally so that people know who you are; as a community that's been burned by misguided research before, someone with a solid presence on PR has a much better chance of recruiting patient-volunteers down the line.

    Especially if you're just collecting genetic information for now, I'm sure you'd have a rich source of volunteers here... especially if your goals were well-defined and made public somewhere on PR. I wouldn't do that just yet, until you've established a presence.

    -J
     
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  16. adreno

    adreno PR activist

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    If you could post a short list of the known SNPs involved, I'm sure a lot of us would be interested in looking them up on 23andMe.
     
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  17. stripey14

    stripey14

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    HI Adreno

    Great question and one I get often. I need to post a FAQS section on the website when I get a spare moment. I might include some of this answer :)

    I would LOVE to be able to do that, unfortunately, that is where we have to start-we have to match SNPS with with clinical findings (the genes are TNXB, CYP21A2, C4). Also unfortunate, the RCCX which contains these genes is very unique because it mutates often, it is riddled with peudogenes and retrotransposons, it has unique mutations spanning 2 genes and genes travel together, allowing 2 rare diseases to appear in one individual at a much higher prevalence than with region in the genome. Probes for the SNPS which have been so far characterized are available commercially for CYP21A2 (for diagnosing congenital adrenal hyperplasia), TNXB (for diagnosing EDS caused by insuffucient amount of tenascin), not sure about C4 and test kits for a contiguous mutation and several other TNXB mutations can be ordered from a commercial company with the scientist who developed them Wuyan Chen PhD available for comments.

    Unfortunately these SNPS are just the tip of the iceberg. 23andme run through analysis will come up with variances of unknown significance, but not even all of them, as analysis of this region involves PCR sequencing and quite a bit of analysis by experts in the RCCX (like Chen). We know about 10% of the population is carrying a CYP21A2 mutation (one of the known ones, known to cause severe enough salt wasting to often be diagnosed early if homozygous), but based on the prevalence of the CAPS profile, I am guessing there is another 10% with variances of unknown signficance (it's similar to the HSP profile which is at 20%). TNXB mutations are in the same boat as they are in the RCCX as well. The characterized SNPS are characterized because they have been linked to haplo-insufficient EDS (AR and AD). This is a rare cause of hypermobile EDS BUT the other mutations will likely cause a wide range of tissue abnormalities from no hypermobility to meeting EDS criteria. We know abnormal tenascin is associated with calcific aortic valves and vesicoureteral reflux, both very common and sometimes associated with hypermobility.

    The most that you can do right now is run your DNA through promethease etc and see if it comes up with a known disease causing variant, not likely but I have contacted by LOTS of people (incidentally with all of the "stuff") who were "lucky" like this, or if you have variants of unknown significance, keeping in mind that these services don't have the sophistication to tease apart this region.

    Very few geneticists do from my understanding. I didn't understand this when I wrote the "Journal Article" last summer. When I first started working with Karen Herbst MD PhD (she is interested because she sees variable hypermobility and CAPS in her subcutaneous adipose tissue disorder patients at a high rate and she is sure that I am right.), she was confident our university lab would be able to work with the RCCX, now with some samples, we are trying to find out. She is encouraging me to network with geneticists with labs who could definitely do it.

    She and I are uniquely poised to do the clinical part of this because I can pick out people with the psych profile and she can figure out what testing needs to be done to demonstrate the hormonal perturbations expected with CYP21A2 mutations. It's not simple testosterone and progesterone, unfortunately. The other issue is that the levels of these hormones are dynamic, depending on whether 21 hydroxylase is overwhelmed or not. We know there is an exaggerated stress response before the enzyme gets overwhelmed and chronic illness starts, so we expect high spiking stress cortisol and low basal cortisol before illness and much lower basal cortisol and still spiking (perhaps) stress cortisol. I also expect low cholesterol and progesterone prior to illness and then high.

    In the future, I may ask people from our FB groups (RCCX and Chronic Illness) to send hormone testing they have already had done so we can design this correctly, knowing which tests give a false impression of being negative (like progesterone and testosterone). Anyway, Karen and will be very good at dividing the patients into different groups clinically, even including people with CAPS and no chronic illness (yet) and then we will need a GREAT genetics lab to characterize SNPS.

    That's a long answer but it probably answers some other peoples' questions, too!

    Also, because our testing is so in depth, we are starting with local (and international for Karen) people from 3 clinics-mine, Karen's and an MD here who treats chronic illness and thinks this theory makes sense of everything she has seen (she treats CERS, Lyme, Toxic mold primarily). I am sure we will need to expand but not for quite a while.
     
    Last edited: May 15, 2016
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  18. Kina

    Kina Admin Support Staff

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    @stripey14 -- could you please edit your post into small paragraphs, many of us can't cope with huge walls of text.

    Thank you. :):):)
     
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  19. A.B.

    A.B. Senior Member

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    @stripey14 you are probably already aware, but just to make sure. The NIH will soon make more funding available for ME/CFS. This could be an opportunity to set up a study to explore this hypothesis further.

    http://www.meaction.net/2016/03/10/nih-aiming-to-commit-rfa-funds-to-mecfs-research/

    PS: Phoenix Rising (PR) may be able to help with some aspects of the study, for example by providing a closed forum in which to discuss study design. Some of our members have a science or research background. A recent product of a PR collaboration was this excellent editorial:

    http://www.tandfonline.com/doi/full/10.1080/21641846.2016.1160598
     
    Last edited: May 15, 2016
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  20. stripey14

    stripey14

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    @A.B. I had heard that, but thank you for the link. Right now, it's just Karen and I trying to write our IRB Protocol and get the word out about the theory. Thankfully, a few people have stepped forward, offering help with fund-raising and applying for grants etc., but they are not quite well enough to get started yet. Between fielding questions, I am gathering a list of places to apply for funding. I appreciate your input-great link!
     
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