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Ehlers Danlos Type 3 Hypermobility - Do you have it?

Discussion in 'Connective Tissue Disorders/Ehlers-Danlos Syndrome' started by Eeyore, May 9, 2015.

  1. Eeyore

    Eeyore Senior Member

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    Many of the EDS types have known genetic explanations, mostly in genes involved in collagen synthesis. However, other than a small percentage of EDS 3 patients who have a mutation in tenascin x, type 3 is not known to be caused by any particular genetic changes.

    I am curious if EDS-3 is actually a secondary phenomenon caused by ME. If you have EDS-3 and ME, which did you have first, and if you got the EDS-3 after the ME, how long did it take, and did you have any sort of pre-EDS symptoms? Was the onset gradual?
     
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  2. Sushi

    Sushi Senior Member Albuquerque

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    As near as I can tell I have always had EDS-3, as did my parents. Aside from the "fun" hypermobility I had as a child, I didn't start getting uncomfortable symptoms from it until a few decades later. Now I need regular care from someone like an osteopath as things just don't stay in place.

    ME, on the other hand, came on much later.

    Sushi
     
  3. Eeyore

    Eeyore Senior Member

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    @Sushi Do you know if you have the tenascin-x mutation or any other collagen mutations? Has anyone ever looked for it?
     
  4. Sushi

    Sushi Senior Member Albuquerque

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    No, I have read about this mutation but have never been tested.

    Sushi
     
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  5. Eeyore

    Eeyore Senior Member

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    Are you confident it's type 3? Do you have stretchy skin or other signs of more classical forms of EDS?
     
  6. Sushi

    Sushi Senior Member Albuquerque

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    I was diagnosed with a physical exam, beighton score, etc. I do have stretchy skin, long limbs and body proportions that are typical.

    Sushi
     
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  7. Eeyore

    Eeyore Senior Member

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    @Sushi - But yours is hypermobility type, and not classical? Usually stretchy skin is found more in classical. I know someone well who has EDS 3 and has no stretchy skin at all, but constant joint dislocations and subluxations, and she has a lot of musculoskeletal pain, TMJ, etc.
     
  8. Sushi

    Sushi Senior Member Albuquerque

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    I seem to fit the hypermobile type better than the classical, but who knows?
     
  9. Eeyore

    Eeyore Senior Member

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    Thanks @Sushi. I'm just trying to figure out if type 3 in ME is inherited or induced (i.e. if inflammation degrades joints/cartilage, etc.) I don't have EDS - I'm definitely not hypermobile, and when I bend over to touch my toes standing I'm about a foot short of the floor...

    Over the last year and a half, however, I've noticed more joints clunking around and it feels like my joints are getting looser or something, and I get more joint pain in general, and more crepitus (cracking). I was wondering if the ME is causing this through some pathologic process.

    Yours sounds like the EDS was definitely first, and the ME followed - and you had it all your life - so that doesn't fit my theory. That's why I figured I'd ask.
     
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  10. Ema

    Ema Senior Member

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    Me too. Always hypermobile but not sick until adulthood.

    No stretchy skin though lots of subluxations, especially in my neck.
     
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  11. Valentijn

    Valentijn Senior Member

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    I've been hypermobile ("double-jointed") all of my life. My mother is as well, but not as much. My knees and elbows bend backward a bit, and I can easily place my palms flat on the floor with straight legs (despite being obese). I can also touch my thumbs to their respective forerams, though it's a bit painful to do so, mostly due to inflammation. I used to be able to bend my pinkies backward to touch the top of my forearm, but swelling and/or aging prevents that now.

    My larger joints do seem even looser now in general, but that could be due to reduced muscle mass as a result of ME-induced sedentary behavior. My joints also seem a bit "drier" now when they crack, and some joint issues started shortly before or after moderate/severe consistent ME onset. My knees started cracking going upstairs about a year prior to onset, and left jaw started cracking then as well. Though now sometimes the left jaw is constantly uncomfortable and almost immediately crackable after each prior crack - maybe related to periods of inflammation or similar.

    I'm obviously not slender, but don't think I'm particularly long-limbed either. My mother also isn't long-limbed, though she is slender. Also no stretchy skin.

    So in my case the hypermobility seems life-long and genetic, though I wouldn't be surprised to discover that ME/SEID can exacerbate or alter the problems associated with hypermobility.
     
    Last edited: May 10, 2015
  12. RosieBee

    RosieBee Senior Member

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    I had hypermobile 'double jointed', bendy body etc etc all my life - developed illness in adult life that was diagnosed as ME 24 years ago.

    Just a few weeks ago I had a diagnosis of POTS and am being referred on to gentic testing for EDS due to the clinical history of not just myself but also family members. No stretchy skin any where! But family history of severe loose joints requiring surgery, aortic aneurism, early heart attack, severe diverticulitis requiring surgery, subdural haematoma - all point to genetic predisposition.

    Ill health came on big time after severe flu and subsequent crashes following vaccinations and infections. Now Lyme disease is part of the picture too - it may have been all along, who knows? And Lyme borrelia has the capacity to weaken collagen structures in the body - is that the kind of thing you might be thinking @Eeyore ?
     
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  13. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Dear Eeyore,
    I don't think EDS-3 is likely to be secondary, for various reasons. EDS-3 is, as you say, not a specific genetic defect, but merely a rag-bag of all the people who qualify on the grounds of hypermobility judged by a Beighton-based scored. In fact the definition keeps shifting around to suit the 'experts' in the field so sometimes stretchy skin is considered a feature and sometimes not. Around 1977 I was involved in a study of what was then called benign hypermobility syndrome (now near enough EDS-3), defined as a state of joint hypermobility without non-joint features. We looked to see if there was mitral valve prolapse. Of course if we had found it we would just have moved the goal posts because then the people with it would have to be excluded from the diagnosis. This sort of circular research has been a repeating feature.

    My own feeling is that EDS-3 is a rather misleading term, since it implies some homogeneity when there is none. I prefer hypermobility - period. I am not sure that it is even a syndrome since the vast majority of people who qualify (about 10% of the population) are completely healthy until they get aches and pains like everyone else as they get old.

    When we did a hypermobility clinic in 1977 not a single patient had any symptoms of ME to my knowledge. Certainly not a single patient had disabling fatigue. That presumably means that at least 90% of hypermobility/EDS-3 is not associated with ME. The same hypermobility clinic in recent years has had a high proportion of patients with fatigue or widespread pain, presumably because of selective referral now that the two are considered to be associated.

    Joints cannot really get looser with time (once growth has ceased), unless articular cartilage is worn. Tightness of joints is due to the length of the ligaments and ligaments have no means of getting longer - just as a strop made of sisal cannot get longer - it can only tear apart. But if cartilage is worn then the ligament will seem to be too long, just as a worn bearing in an engine will waggle not because anything has got longer but because the surfaces have got shorter. The only reason I ever saw for joints getting looser in 40 years of rheumatology was surface wear - basically what people call osteoarthritis - or of course ligament rupture, either cruciate or in the shoulder mostly.

    I must say that I find it very puzzling that there should be any relation between hypermobility and ME. There is no immunological issue and no obvious reason why laxity should relate to fatigue. Ballet dancers exercise maximally for 8 hours a day and most of them are hypermobile. There might be some link in terms of neural reflexes I suppose but it is hard to see how that would relate to the sudden development of fatigue after a viral infection.
     
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  14. lansbergen

    lansbergen Senior Member

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    Before my disease reached the worst point I strained my ankles frequent for no reason. Knees, elbows, shoulders and even vingers did strange things too. Could that be misinterpreted as EDS? Over time it has gone back to normal.
     
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  15. Valentijn

    Valentijn Senior Member

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    Maybe someone could start a poll? Perhaps in the general symptoms subforum so that people who aren't interested in this subforum will see it and respond as well.
     
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  16. Eeyore

    Eeyore Senior Member

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    @Jonathan Edwards -

    I agree it's one of the more perplexing disease associations in ME. It makes a good deal more sense with POTS, where problems with collagen structure could create vasculature weakness resulting in venous pooling, which might make one more susceptible to ME (i.e. a compounded effect of weak collagen and poor autonomic function). It could be that ME occurs to varying degrees after infections in many people, but compensatory mechanisms are sufficient so that it remains subclinical. This fits with general heterogeneity of disease severity in ME, which ranges from very mild / annoying to debilitating.

    Dr. Edwards, can you think of any immune mechanism by which collagen could be degraded, resulting in joint loosening? I know you have vast experience with RA in particular. An overactive immune system does have the potential, sometimes, to produce elevated levels of matrix metalloproteinases, many of which can degrade collagen. Does this collagen degradation itself not have a clinically significant effect, or does it just not manifest as joint laxity (and is it possible that erosive bone damage and joint stiffness in RA make it so you can't see laxity anyways)? Have you ever seen joint laxity coexist with RA, and if so, did the RA alter it in any way, either increasing or reducing it?

    I suspect you are already aware that in RA, they sometimes now test 14-3-3 eta levels, which correlate with disease severity in RA. Generally, 14-3-3 activates MAPK family proteins (ERK1/2, c-jun) resulting in increased transcription of IL1 and IL6 - the latter of which, in particular, should increase CRP. 14-3-3 eta also induces MMP-1, which is a collagenase, and several other MMP's as well. I know we're now discussing a different disease entirely, but curious if cartilage degradation by activated immune cells could play a role in joint laxity (even though, we'd then have to explain the lack of CRP elevation in these patients - as far as I know, and I could be wrong, there is no general elevation of CRP in hypermobility syndromes).

    Clearly ME is not responsible for all cases of "type 3" hypermobility, nor is the converse true (I'm ME w/o EDS, and I know people who are EDS w/o ME). I'm actually pretty inflexible, and not because of pain - I'm just not that bendy. My sister because pretty flexible but that's after a lot of yoga (can put palms flat on floor, etc. - but still wouldn't have a very high beighton score, as arms/legs don't bend past 180, fingers don't bend to arm, etc.) I agree with you in general that type 3 is a hodgepodge.

    I read once that men tend to have less EDS because musculature compensates better, and when they have it, it can be later onset. I wonder if something similar is in play for ballet dancers - as long as they stay in peak condition, the strain is born by muscles rather than joints (at least partially).

    I'm not sure how much all of this makes sense, and it's just a loose theory that formed in my head last night - there could be more holes than in a block of swiss cheese - but it seemed interesting. It does seem, based on other posters, that the EDS precedes the ME, often by many decades, and that the EDS is usually lifelong, whereas the ME is not. That would argue against any causative role for ME in producing EDS, and suggest rather that EDS may create a predisposition to ME - but I don't know why. Alternatively there is a common risk factor for both, and they manifest differently or at different times.

    Does anyone out there have genetically diagnosed non-type 3 EDS and also have ME? Or Type 3 genetically confirmed to be tied to Tenascin-X?
     
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  17. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Immunologically driven synovitis, as in RA, or psoriatic arthritis, can certainly lead to articular cartilage loss. However, the story in the books is probably wrong. TNF, IL-6 and IL-1 will all stimulate metalloproteinase production but the interesting thing is that you can have repeated attacks of brisk inflammation in a joint with no cartilage loss. The reason for this is not fully known. One factor is the presence of inhibitors such as TIMPs. However, I suspect that a more important factor is the presence of a 'surface halo' of proteoglycan at live cartilage surface - PG is constantly being extruded from cartilage surface a bit like grease from a grease gun. It may be that the highly sulphated GAG chains neutralise the proteases. However, if chondrocytes die no more PG is produced. My own histological experience is that cartilage is resorbed in RA only if it is already dead. Ironically it probably dies because of TNF and IL-1 all the same because these cytokines greatly increase synovial cellularity and metabolic demand and cartilage is totally dependent on glucose left over after synovium has had its share. In RA glucose goes low and sometimes to more or less zero in the joint. So I suspect that cartilage dies when TNF levels reach a critical level that leads to chondrocyte hypoglycaemia (they depend on glycolysis).

    The long and the short of all this is that you do not get cartilage damage until synovial inflammation is severe (when the CRP should be up). In condition where synovitis is low grade, like lupus, cartilage is usually not affected. This may not be a hard and fast rule but the level of cytokine activation seen in ME is unlikely to be enough to account for cartilage damage.


    Fewer men will qualify for hypermobility syndrome simply because of anatomical differences in bone structure. The elbow is the most different. Women have a greater carrying angle and normally have a few degrees of hyperextension whereas men do not. Female hips also have a wider range of movement because of pelvic shape. Lots of little girls can do the splits but very few little boys. There really ought to be different scoring criteria for the two sexes.
     
  18. Eeyore

    Eeyore Senior Member

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    Thank you @Jonathan Edwards for that explanation.

    Another follow up question: Which immune cells are the direct effectors of cartilage resorption? Is this just macrophages just performing housekeeping after cartilage is already dead? Would it make any sense that in RA, this aspect of the immune system is normally regulated, and so there is no destruction of living cartilage, but, potentially, there could be other forms of immune dysregulation in which the normal inhibition of MMP's and cartilage resorption is not functional? (Obviously a broad question and pretty hypothetical.)

    Dr. Jay Goldstein (a clinician with many years of experience treating ME patients) noted that many of his patients had highly elevated levels of tPA and reduced PAI-1, both of which are intricately connected with the network of MMPs and TIMPs. I wonder if this is paralleled with elevation of MMPs (which Dr. Shoemaker has noted in his patients - although to the best of my knowledge he has not mentioned TIMPs). I'm not really an adherent to Dr. Shoemaker's mold theories, and I can't vouch for the labs he uses in testing MMPs, but perhaps they truly are elevated.

    This would imply, possibly, some degree of a progressive nature to ME, which I'm not sure we see, at least most of the time. My own course is more relapsing / remitting, but of course many autoimmune diseases follow different courses in different patients.
     
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  19. Apple

    Apple Senior Member

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    I don't have EDS. I'm not even remotely hypermobile and never have been, but I have had several subluxations over the past several years. My GP states that because my muscles etc are weak, "things will just pop out". Not sure how true that is, but if so, I could certainly see how M.E could exacerbate and highlight an underlying connective tissue disease due to the lack of support around already hypermobile joints.
     
    Last edited: May 10, 2015
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  20. Snow Leopard

    Snow Leopard Hibernating

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    Most of the patients I know do not have joint hypermobility. *shrugs*
     
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