One Gene Many Disorders: Genetic Finding Could Help Explain POTS, EDS, IBS, FM, ME/CFS and Others

Discussion in 'Other Research' started by Cort, Oct 20, 2016.

  1. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    First, at least for me, there was chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). Then I learned about irritable bowel syndrome (IBS), then POTS and in the last five years Ehler’s-Danlos (EDS) and Mast Cell Activation Syndrome (MCAS).

    The more researchers looked the more they seemed to uncover a large group of syndromes which tended to flock together. Anyone who has ME/CFS or FM now has to consider whether they also might have dysautonomia, IBS, POTS, MCAS and a host of other disorders (interstitial cystitis, migraine, multiple chemical sensitivities, small fiber neuropathy).

    Obviously, this suite of disorders is connected somehow, but the question - what is the tie that binds? – has remained. The wide range of symptoms – from flushing to gut problems to chronic pain to orthostatic intolerance to connective tissue problems – had defied understanding – and helped psychologists to get their feet in the door.

    Now the NIH of all groups – never really a friend to any of these - may have uncovered a link - that may explain them for some people.

    Family Study

    Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. © 2016 Nature America, Inc. All rights reserved.

    The researchers did what a Simmaron Research Foundation study is currently doing with ME/CFS; they zeroed on a set of families with these problems and studied them intensively. First, increased levels of an immune factor called tryptase which is sometimes associated with mast cell activation showed up. Researchers did not find signs of altered mast cell growth or morphology or increased IgE degranulation or tryptase expression; i.e., they said they found no indication of mastocytosis or mast cell activation disease (MCAS). Despite the high tryptase levels they believed the disease they uncovered was more akin to connective tissue disorders such as Ehlers-Danlos Syndrome (EDS) than MCAS.

    Of the 96 people from 35 family’s studies, almost 50% met the criteria for IBS, 65% met the criteria for chronic gastroesophageal reflux, 28% had joint hypermobility, 48% had arthritis, 47% had headache, or body pain, a full quarter had congenital skeletal problems, 46% had autonomic issues and 34% had POTS. Other common issues included flushing and pruritus (51%), itching and sleep disruption (39%) and exaggerated reactions to venom.

    Fatigue wasn’t measured but since fatigue is common in all these disorders, it was likely quite high. (Many of these individuals probably would have met the criteria for fibromyalgia or chronic fatigue syndrome (ME/CFS). )

    Extra Sequences Spell Trouble

    The group’s genetic secrets were not yielded easily. First exome and genome sequencing found no common gene variants but a linkage analysis identified a single “peak” on one chromosome – a section of the chromosome containing the 4 genes responsible for producing tryptase.

    Further testing found that individuals containing multiple copies of a tryptase encoding sequence were highly, highly, (highly) likely (p<.000001) to have high tryptase levels. This is the kind of probability that’s probably considered a slam dunk in genetics; everyone who carried multiple copies of this tryptase-producing sequence had high tryptase levels and a wide range of sometimes bizarre symptoms. Plus, the more copies of the copies of the sequence an individual had, the worse they were off symptomatically. None of the family members without these sequences had any symptoms.

    Tryptase is the most common enzyme found in mast cells and is often used as a marker for mast cell activation. Interestingly, none of the individuals had evidence of mast cell activation syndrome. If tryptase was causing their symptoms, it was doing so in a different way than is ordinarily associated with MCAS. (MCAS is apparently called a syndrome for a reason.).

    After identifying a genetic anomaly associated with high tryptase levels in families it was time to see if it showed up in other groups. A retrospective analysis of people who’d had genomic analyses done for other disorders indicated that all the individuals with increased serum tryptase levels had multiple copies of the tryptase encoding sequence.

    Next, the researchers turned to a healthy control group, and again found that all the individuals with increased tryptase levels had multiple copies of the tryptase encoding gene. (Three of the “healthy controls” turned out to have similar symptoms as the original cohort; the rest were either normal or had minor problems).

    New Disease

    It’s rare that genetic effects are so clear. In fact, the genetic effects were so clear that the condition is now called hereditary-a tryptasemia. This disease is “exclusively caused” by increased copy numbers of the tryptase-producing sequence.

    Exactly how elevated tryptase levels are causing pain and autonomic nervous symptoms is not clear but may involve “protease-activated 2 receptor pathways” (if that’s any help (lol). The study highlights, though, that it’s not necessary to understand a disease to find a treatment for it. Knowing that elevated tryptase levels cause pain, connective tissue problems and orthostatic intolerance, even if we don’t know how, can allow researchers to develop anti-tryptase blockers that could conceivably stop these symptoms in their tracks.

    Tryptase can be tested for, and in fact, around five percent of the population, or over 15 million people in the U.S. have high tryptase levels. Most of them are probably asymptomatic but those who are ill could benefit greatly from this finding. It's very rare to find such a clear genetic link and such a clear treatment pathway.

    NIH Admits It Was Not All in Their Head After All

    The NIH itself noted that this study should give hope to people with complex multi-system disorders who, too often, have ended up being told their unusual symptoms must be “all in their head”. It was obviously high on this work. It’s not often that a clear cause of an illness – let alone a spectrum of illnesses – may have been found. In fact, the NIH was so excited that it produced a video about the finding, and sent out a press release featuring none other than our old “friend”, Dr. Anthony Fauci, the Director of NIAID.

    Chronic fatigue syndrome’s relationship with NIAID and Fauci is a complex one; NIAID is the only Institute to ever fund ME/CFS research centers, but its abandonment of ME/CFS in the early 2000’s ushered in 15 years of declining funding. That obviously didn’t endear anyone to Fauci or NIAID, but now NIAID and NINDS do appear to be doing the lion’s share of the work in the ME/CFS Working Group at the NIH.

    Plus, seeing NIAID crow over its genetic finding for a complex multi-symptom condition is a good thing. One of the reasons NIAID abandoned ME/CFS was because it was a complex multi-symptom, multi-systemic condition. The multiple system issue gave NIAID an out; because ME/CFS clearly wasn’t simply an immune disease it decided it was no longer responsible for it. Fifteen years later, ironically, as NIAID begins to welcome ME/CFS back, it has found an immune factor that causes multiple symptoms and produces a multiple system disease.

    Next up for this group: developing a diagnostic test to detect alpha tryptase gene copies and finding ways to block tryptase production. For people with extra copies of this gene and who are ill the news is good indeed. Few diseases, after all, can be traced to one factor. Pharmaceutical companies are surely combing their drug databases for drugs with tryptase-inhibiting pathways.

    Thanks to The SolveME/CFS Initiative for highlighting this study on their website. Without their doing that, I would have missed it entirely.
    Last edited: Oct 22, 2016
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  2. Remy

    Remy Administrator

    The thing I'm having trouble with it that tryptase is typically "normal" for most people with MCAS much less MECFS.

    It's not at all unusual for the level not to be elevated. Mine was perfectly normal. That's why Afrin et al often try to test other, even more difficult and unstable mast cell mediators to try to catch some elevations.

    So how is this going to be a useful marker if it often comes back normal in the face of overwhelming clinical symptoms?
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  3. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    I didn't know that although I may have heard that. It is used to diagnose MCAS at times, but it's one of several diagnostic tools for MCAS.

    A 2013 review stated this

    But it is a good diagnostic tool for this new disease - which you apparently don't have. Tryptase levels are always high in this group - which doesn't have some other features of MCAS...(Since they didn't check for all of the features associated with MCAS it's possible that they do have some of them.)

    This could end up being a great way of differentiating out different types of MCAS - one of which involves high tryptase levels but not other things associated with it.
    Last edited: Oct 22, 2016
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  4. h3ro

    h3ro Active Member

    Your mentioning of MCAS early in the post makes it seem like MCAS is one of the diagnoses that are related to this newly identified disease. It's a little confusing.
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  5. san

    san New Member

    would my 23&me results have this genetic information?
  6. JWest

    JWest Member

    Looking at the study I don't think so. It talks about the gene but doesn't mention any SNPs which are what 23&me reports.
  7. Marline Emmal

    Marline Emmal New Member

    Cort, you mention flushing as a symptom. Is there a way to distinguish this flushing from the flushing caused by carcinoid syndrome?
  8. san

    san New Member

    Ah got it, thanks!
  9. Lissa

    Lissa Well-Known Member

    I am also a tad confused as some of the symptoms described actually seem to be things that are (or can be) associated with MCAS. Flushing, POTS, autonomic issues, IBS, etc.
  10. Darden Burns

    Darden Burns Member

    This study is very exciting and coming from the NIH of all places - very encouraging. I have elevated tryptase levels but no symptoms of mast cell activation. I've been diagnosed with EDS hyper mobile type and also have IBS, poor muscle recovery and a history of chronic fatigue. I am optimistic that these genetic findings may lead to effective treatments!
  11. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    Got it.

    It is actually related in an important way. If you have high tryptase levels then some doctors will diagnose you with MCAS and they will try to treat it and their treatments probably won't work. I say probably because while there is some evidence of increased spontaneous mast cell tryptase expression. In a way, it is MCAS because the tryptase is coming from the mast cells.

    The authors did not do a full MCAS analysis - didn't look at prostaglandins or histamine metabolites or other substances, but obviously believe it's quite different (they called it a new disease) but I don't think we know the full connection.

    In my book, this is one form of MCAS. Anyway, besides POTS, IBS, MCAS and other diseases to be aware of there is now hereditary-a tryptasemia.
    Last edited: Oct 22, 2016
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  12. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    It looks like it will take a specialized test. To my understanding 23andME identifies gene polymorphisms - small changes in the genetic code - but not changes in the numbers of copies of a sequence. It's the number of copies that makes the difference.
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  13. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    I think what the research is saying is that these symptoms can be caused in several different ways. If you look at diseases like POTS - of which there are several types and which can be caused in several ways - which shares symptoms with MCAS and ME/CFS - it's not surprising to see another way to produce POTS to pop up.

    I know someone who with problems with PEM, flushing, autonomic issues and IBS who has not been diagnosed, so far as I know, with MCAS.

    Over time I would be surprised if more ways to cause this suite of symptoms don't show up. This is just another way to produce them. People who have high Tryptase levels and these extra copy sequence may be very, very lucky because there may be a straight shot to an effective treatment. (Just bring the tryptase levels down.) That's pretty unusual in medicine.

    Who knows what we'll find with something like ME/CFS! These familial studies are really good at picking up genetic causes or contributors to disease. I think two are going on right now in ME/CFS - one funded by Simmaron and one with the Bateman-Horne Institute...It'll be interesting to see what they will find.
    Last edited: Oct 22, 2016
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  14. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    I'm afraid I have no idea - sorry.
    Last edited: Oct 22, 2016
  15. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    This could be you Darden! I hope so. I imagine that pharmaceutical companies right now are digging through their drugs - approved and not approved - looking for tryptase inhibitors. :wacky:
    Last edited: Oct 22, 2016
  16. Gail C

    Gail C Member

    Hello Cort and all.... long time lurker, and first-time poster here. This thread made my decision to join the Forum. I think the subset described is me as well. I actually contacted NIH about this study because I have high Tryptase, as well as H POTS and Hypermobility. I was turned down because no one else in my has been diagnosed, and they wanted families. However, I have tried to follow the research as closely as I could, and thought I would share what I know.

    The folks at NIH know that there are people out there who have symptoms that are also linked to Hereditary Alpha Tryptase, so try not to be concerned that they will not be looking at this group. I think they will because they want to know the root cause. It simply may be that about 45% of Caucasians are Alpha Tryptase deficient, and it is the luck of the draw so to speak.

    "What happens if my tryptase level is normal, but I have these symptoms and/or so do multiple other family members?

    There are many people who do not have hereditary alpha tryptasemia syndrome but do have all of the symptoms listed above. We do not know yet the association, but this is an area of active research."

    While POTS, EDS III or Hypermobility, and high Tryptase definitely cluster together in a certain group of people, it doesn't seem NIH is ready to say it *causes* H POTS. At this time, according to some folks who were in the study, people who treat both POTS symptoms and MC symptoms do better. It may be that a med that can target Tryptase solely will help, but I am not holding my breath for that one. I think upstream genes will be the answer, with the disclaimer that I am not a geneticist!

    BTW, there is already one supplement on the market which is reported to be a potent Tryptase suppressor. It is called Lactoferrin. I have been reading about this and think I am going to do a trial as it seems safe.

    Hope this post helps someone out there.

    Last edited by a moderator: Oct 23, 2016
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  17. dejurgen

    dejurgen Well-Known Member

    I doubt my doctors did an MCAS or tryptase test as it seems to be unheard of here. Some parts of my disease seem to be inherited on both sides, so who knows I might be lucky and find a treatment soon...

    But the most important thing for us all may be this: the "it MUST be all in your heads" hypothesis/lame excuse is utterly broken now if these results get repeated. That opens the path for at least three things:

    A) Critical re-analyses of all things related to CBT/GET/PACE as it is in no way any longer the most scientific explanation

    B) It gets far more easy to approve funding for broad big-data analysis of inherited syndromes of all kind. The ones not related to ME/CFS should be particularly easy to approve. As many doctors/agencies are still afraid of dabbling into ME/CFS territory it may be wise to advocate for this type of research rather than direct ME/CFS research now. It reduces involvement risks for agencies and researchers while the result may yield a strong and growing understanding of our disease leading to:

    C) Once more things like this are uncovered, going all in on ME/CFS research may become the only logical thing to do. It may be a quicker route to pass through B) than to go the direct route.
    Last edited by a moderator: Oct 23, 2016
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  18. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    Welcome to the Forums and it's great to have someone with first-hand knowledge of this. I think this from the FAQ demonstrates how complex this situation really is - The FAQ's are really good. I wish I had this page when I did the blog (lol).

    Here's a cutoff point for tryptase
    A Kind of MCAS? It seems that people with this genetic problem do respond to mast cell inhibitors at times
  19. Cort

    Cort Founder of Health Rising and Phoenix Rising Staff Member

    I agree - I think it's astonishing that one gene and one immune factor appears to have such a broad effect in some people.

    How great it would be if the NIH would fund big data analyses of all these disorders. We would learn much...Maybe they will be more amenable to that.
  20. Gail C

    Gail C Member

    Thank you Cort. I try to keep up with what is happening in the ME world as well. I truly believe I have ME but have never pursued the diagnosis due to all controversy...and the cost to see someone who something about it, and the travel, and so on. The recent research is giving me hope that one day things will become much easier for folks.

    Yes, some do have MCAS. I am in that category because I have elevated Tryptase, with no other signs of Masto, but have MC activation. The paper from Vandy, which first published the coexistance of Mast Cell Activation and H POTS, may have also given the answer as to why this happens. They noted that Neuropeptide Y (NPY) is coreleased with Norepinephrine (NE). NPY degrangulates MCs. But the paper does not really explain why we have too much NE. Cromolyn Sodium helps stablize MC activation for me, while Clonidine reduces NE output.

    "In this regard, neuropeptide Y (NPY), a 36-aa neuropeptide that is coreleased with norepinephrine from noradrenergic neurons, has been shown to induce mast cell degranulation with the release of preformed mediators in purified rat peritoneal21,22 and human jejunal mast cells23 and to induce hypotension in animals secondary to MCA in vivo.24"

    Then there was the fairly recent finding that some folks with H POTS have elevated Angiotensin II (ANGII). ANG II upregulates Transforming Growth Factor Beta (TGF-Beta), a cytokine. Elevated TGF-Beta has already been found in some EDS groups, and treatment to reduce this helps.

    It is complicated and convoluted. I keep collecting test results showing elevated levels of whatever. So far...NE, Tryptase and TGF-Beta. We obviously have Immune System problems, and I am just not sure Tryptase can cover it all.

    FYI... when I read your summary of your 23andme results, I thought...Wow, I could have written that post! The exception is that I am not Lactose Intolerant. Or maybe that was your twin, and I have it mixed up. My sleep study, which I had done before 23andme had already told me I had a reduced amount of deep sleep, along with about 1/4 of the normal amount of REM sleep and more movement that usual. So definitely an inherited pattern I would say.

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