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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. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Resorption is almost certainly mediated not by immune cells but by resident fibroblasts, which are the main source of metalloproteinases other than the neutrophil specific one (I forget which one ?MMP-9). Bascially I see cartilage removal as a bit like fracture healing - clearing up rubbish by stromal cells irrespective of any immune activity. I find it hard to see how an immune reaction would disrupt the normal protective mechanism of cartilage integrity directly. There is a condition called relapsing polychondritis in which there is an immune response to cartilage itself, but most of the damage occurs not in joints, where PG is being extruded, but in places like the nose and ear where cartilage is in direct contact with perichondrial cells.
     
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  2. Eeyore

    Eeyore Senior Member

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    Ok thanks @Jonathan Edwards.

    MMP8 is a neutrophil collagenase, but I think MMP9 is also contained in neutrophils.

    This idea probably doesn't have legs - but I thought I'd explore it and ask a few questions, and appreciate your input.

    I'm still very confused as to the connection between ME and EDS / hypermobility. I'd love to see a good study done, and to look at whether it's all type 3 hypermobility or if a genetic cause can be determined for many of them.
     
  3. Sushi

    Sushi Senior Member Albuquerque

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    Autonomic specialists seem to think that there is some connection between dysautonomia and EDS in that so many of their patients also have EDS. They also find a correlation with mitral valve prolapse. Perhaps the vein valves in the legs are also affected by some forms of EDS leading to backflow and exacerbating OI? Just possibilities....

    Sushi
     
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  4. justy

    justy Donate Advocate Demonstrate

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    I was diagnosed with EDS III recently - it is a lifelong disorder - I am not very hypermobile either!

    KDM says about 30% of his patients have M.E and EDS and we do see a lot of people with both around here. I also have MCAS - which also seems to be common in people with EDSIII.
     
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  5. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I must have meant MMP-8. I wrote papers on this stuff but my head is a sieve for numbers.

    I'd love to see some good studies done too, but it is a field full of a lot of uncontrolled data unfortunately.
     
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  6. Lisette

    Lisette Frida For All

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    Hi, Eeyore

    I have wondered the same thing about hypermobility causality-- which came first? In my case they seemed to come together. I am not double-jointed, bendy, hyper-extendy, etc. No mitral valve prolapse (I had a heart scan for another issue) nor stretchy skin.

    When I first heard "Ehlers-Danlos" applied to me was during a long and puzzling back injury. During this time it was noted that I had the "look" about me-- tall and slender with a wide wingspan. But I didn't have the "classical signs", so this confused them and they dropped it.

    So the name became less important to me, than the desire to understand collagen formation and connective tissue disorders. We all just focused on the joint hypermobility and dysfunction and called it that.

    As the E-D question was being discussed among my back and pain specialists, I was diagnosed with FM and then CFS about eight months or so later. My ability to walk and bend over and sit fully upright had been resolved, but my general health was falling apart.

    I had the eighteen or more tender points of fibro, and all sorts of deregulated systems acted up chills and dysautonomia set in. And all of this happening _while_ I was doing the prescribed graded exercise therapy for my back.

    Imagine going through CBT/GET _before_ getting CFS, which prevents you from being able to drive to CBT or do the GET. :-o That was a real head-spinner.

    I haven't tried to force connections between the dots, and accept that there could many coincidences rather than comorbidities.

    But sometimes it's hard for me not to notice that I was highly mobile (healthy), got hurt and became hypermobile, and then got sick and became highly immobile (bedridden). :-/

    I appreciate your bringing up this question. It is perplexing.
    Lisette
     
  7. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I fear that a lot of this talk about EDS 3 is doctors covering up their ignorance by using clever sounding terms. If you are not double jointed or hyper-extendy then I cannot see how you can be described as having hypermobility or EDS3, Lisette. I was involved in the original mitral valve prolapse study and the truth is that we found no real difference in people with hypermobility - and this has been confirmed since. The link to mitral valve prolapse is a myth I am ashamed to have been involved in propagating. Stretchy skin is just the opinion of the doctor - I had to 'measure' it myself and I never knew how to score it. Being tall and slender with long arms is entirely normal and as far as I know nothing to do with EDS3 - it is a feature of Marfan syndrome but that is something completely different.

    I don't think we have any reason to think EDS3 actually exists as a specific disease. It is an ill defined pattern of joint laxity and maybe skin laxity that is probably based on a vast number of different combinations of minor variations in connective tissue genes. If someone becomes hypermobile later in life that must be something quite different since EDS3 is by definition genetic if it is even worth having such a name.
     
  8. Hutan

    Hutan Senior Member

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    The following presentation is interesting (although will be frustratingly slow-paced for all you experts in POTS and ME/CFS).



    Associate Professor Chris O’Callaghan is a clinical pharmacologist and general physician at Austin Health, Heidelberg. A/Prof Chris O’Callaghan heads the Blood Pressure Disorders Clinic at Austin Health which specialises in treating patients who have impaired ability to control blood pressure, which produces many of the symptoms seen in ME/CFS such as faintness, lightheadedness, impaired concentration, ‘anxiety’ type symptoms and palpitations. Conditions that result in impaired blood pressure control include spinal cord injury, disease of the autonomic system, fatigue disorders such as ME/CFS and disorders of connective tissue elasticity such as joint hypermobility syndrome and Ehlers-Danlos Syndrome. Associate Professor O’Callaghan is the author of many scientific papers and an active researcher of cardiovascular disease.

    So, I think AP O'Callaghan is saying that both ME/CFS and EDS/hypermobility can result in an impaired ability to control blood pressure. And a person with both ME/CFS and hypermobility may well have less ability to control blood pressure than a person with ME/CFS alone.

    My son and I will both be seeing AP O'Callaghan in the next couple of months regarding our orthostatic issues. (We are both pretty flexible (thumbs bend back to wrists easily) and have ME).
     
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  9. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I have to admit to being confused by all this. As I understand it POTS is an inability to control heart rate rather than blood pressure - one definition says that blood pressure does not fall in POTS.
     
  10. justy

    justy Donate Advocate Demonstrate

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    I am surprised that you think that considering EDS Support UK has this to say about EDS HT (formerly called EDS III according to their website)

    http://www.ehlers-danlos.org/about-eds/types-of-eds/hypermobility-ehlers-danlos-syndrome/

    EDS Support UK has the following medical advisors:

    Professor Aziz Neurogastroenterologist

    Dr Jane Simmonds MCSP MMACP FHEAPD, MA, PGDip, BApp Sc (Physio), BPE Physiotherapist

    Dr Nigel Burrows Consultant Dermatologist

    Dr Alan Hakim Rheumatologist

    Mr Vik Khullar Gynaecologist

    Professor Rodney Grahame Rheumatologist

    Professor Chris Mathias Neurovascular Professor

    Angela Hunter Speech and Language Therapist

    Anthony I Attwood, MBBS, FRCS(Ed), FFSEM (RCP&SI) Consultant Plastic Surgeon

    Dr Glenda Sobey EDS National Diagnostic Team

    Professor Peter Beighton Geneticist (retired)

    Professor Francis Michael Pope Geneticist (retired)

    Helen Cohen Consultant in Chronic Pain Medicine and Rheumatology -

    Dr. Clair Francomano Geneticist.
     
  11. Hutan

    Hutan Senior Member

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    @Jonathan Edwards
    Yes, I expect the wording should be 'an inability to appropriately control blood flow'. I guess in healthy people blood pressure and heart rate (edit - and blood volume) interact in a coordinated way to get blood to where it is needed.

    Dr O'Callaghan makes the point that many of the distinctions between various orthostatic issues are quite ill-defined and that overall they boil down to a dysregulation of blood flow related to gravity.

    He's also acknowledging the blurriness in criteria related to hypermobility/EDS types - and the difficulty in objectively measuring some of the signs.
     
    Last edited: Jun 21, 2015
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  12. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    Dear Justy,
    The EDS support UK site says pretty much what I said - an ill defined pattern (lots of possible features with nothing definitive, although if it is HT I think there has to be some hypermobility) and probably several genes.

    Several of the medical advisors are well known to me. Hannah Kaz-Kaz took over the hypermobility clinic because the clinical director had asked me if I would do it (since I was there at the beginning when Rodney Grahame started the clinic in 1977) and I said that I didn't think we really had anything useful to offer. Hannah was a registrar of ours at the time, as was Alan Hakim at one time. They keep changing the name of the so-called illness because nobody actually has a clear idea of what they mean by the illness or how you define it.
     
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  13. Valentijn

    Valentijn Senior Member

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    This is often the result of sloppy language. POTS is better known, so it gets used when someone means more general "Orthostatic Intolerance" or a different specific type of low blood pressure. The tachycardia is also easier for patients and doctors to notice, so might be apparent before the underlying blood pressure issues are.
     
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  14. Hutan

    Hutan Senior Member

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    Yes, to illustrate the varied dysfunctions:

    I have POTS (>30 beats per minute increase in heart rate from supine to standing). If I keep standing still, my heart rate will increase, as will my blood pressure.

    On a PEM day, my pulse pressure can drop to 20% when standing e.g. doing the dishes

    Although I have always had slightly low blood pressure, since getting MECFS, my blood pressure can increase after very minor exertion to a level that would be diagnosed as high blood pressure - and it stays elevated for a much longer time than is normal.

    So the particular label of orthostatic intolerance applied can depend on the circumstances immediately prior to seeing the doctor, as well as what the patient and/or doctor is looking for. The important thing is that blood flow is dysregulated and it is related to the position of the body.
     
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  15. Eeyore

    Eeyore Senior Member

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    @Jonathan Edwards - I think EDS is clearly real (as I believe you do) - just that it's overdiagnosed. Most EDS is related to specific known defects in collagen genes. I agree with most of what you are saying - I think there is some bias based on what doctors think they will find. EDS3 is a bit more of a mystery, although at least a subset have mutations (3 known as last I heard) in the TNXB gene (tenascin-X - TNXA is a pseudogene on the RCCX cassette on chromosome 6 and isn't functional). The RCCX is on chromosome 6 in the MHC between HLA-B and HLA-DRB1. I think if we can find an actual mutation in the TNXB gene and correlate to symptoms, then the person does have a form of EDS, or at least some form of hypermobility. It's inherited in an autosomal dominant fashion.

    That said, most with EDS3 diagnoses are negative for all known EDS3 mutations. We need a good study to actually genotype them (sequence the genes). These are very tricky genes to sequence because of the nearby pseudogene with high sequence homology. As such, SNP typing may not give accurate results. Also, the copy number for the RCCX cassette is highly variable, ranging from 0-5, as meiotic crossing over is notoriously error prone when dealing with duplicated and deleted areas of high sequence homology.

    POTS is not about blood pressure - it's about heart rate. I have POTS. When I stand my HR can go to 150, and usually jumps about 50 for a few minutes, then normalizes somewhat. I have syncope on a tilt test without adrenergic stimulation, usually in under 1 minute. This was first noticed in 1997 or so, shortly after I developed ME. My ID specialist read the paper from Rowe et al from Hopkins on the connection between CFS and NMH (neurally mediated hypotension) and decided to order the test. Actually, he was pretty shocked it was positive. I asked him if CFS was real. He told me that a few years prior he would have said no, but he's seeing too many cases that look alike, and look like it, and for which he cannot find other explanations. I have never tested positive for orthostatic hypotension with the standard tests, although it's all over my file - mostly because of confusion by doctors as to what the difference is, and because POTS was only really known by Dr. Low at Mayo and a few others in the mid-late 90's. I did have an unusual drop in bp on valsalva noted by a very talented neurologist at the med school where I did my undergrad work. I improved a great deal on florinef and atenolol, as in the Rowe paper. Later small studies failed to duplicate the efficacy of florinef, but I suspect they were too small and the population too heterogeneous, because the effect was quite dramatic in me. We also documented hypovolemia (>2 standard deviations below normal for my age/gender/BSA - about 2/3 of normal plasma volume, normal red cell mass) by radiolabeled dilution assay at a top university med school. This was AFTER I started florinef! Florinef is the only reason I was able to finish my undergrad, and I take it today. All through the process I've had undetectable vasopressin levels, but no endo has ever wanted to treat with desmopressin as the florinef maintains osmolality better - desmopressin can induce hyponatremia.

    I think the POTS/EDS connection is that if you cannot properly constrict veins in your legs, then you pool blood, which can be compensated for by increasing heart rate - which is what those of us with POTS do. I think the best POTS researchers right now are at Mayo with the exception of Dr. Julian Stewart, who has done some really brilliant work on it at NYMC and published extensively. He has a very useful and information rich website (if not always easily navigated).

    I do not have EDS. I do have POTS. My mom had ME when she was 15 for about 2 yrs, but recovered (mostly). At that time she developed POTS. She still has that - but she has no abnormal reaction to exercise, which I consider the defining feature of ME. She and I run low bp in general, we increase HR on standing, and we experience syncope and presyncope. My maternal grandmother also required florinef or experienced extensive syncope, although not until later in life (70+). She had labile bp (as do mom and I - e.g. all 3 of us have/had systolic bp move over 100 points in a day in the absence of exercise).

    My father, sister, and remaining grandparents are/were unaffected, both in terms of ME and POTS. In this case, it seems to pass as autosomal dominant or possibly X-linked dominant (men/women affected equally).

    Thus, if POTS were caused by EDS3, then it is peculiar than mom and I do not have hypermobility. I think my Beighton score was like 1-2 (out of 9). Mom is in her 60's and has absolutely no joint paint complaints of any kind. My maternal grandmother had a bit of osteoarthritis but generally was in very good health until her death at ~87 and said she never had any pain. So in our case, we have familial POTS with possibly simple mendelian inheritance in the absence of EDS or hypermobility.

    That doesn't mean hypermobility affects some with POTS or that it's not a cause of some cases of POTS. Most POTS docs describe subsets. I'm not sure if any of Dr. Stewart's research (very high quality stuff, and published/peer-reviewed) has identified EDS in some but not other subsets, or at varying frequencies.
     
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  16. Hutan

    Hutan Senior Member

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    This raises so many questions.

    What percentage of people with ME have an orthostatic intolerance issue (including but not limited to POTS)? What percentage of people without ME have an orthostatic intolerance issue? What percentage of people with ME have joint hypermobility and related conditions vs the rest of the population?

    When did the orthostatic intolerance issue first start (prior to ME onset; at onset; sometime after)? (Perhaps, as in my case, there were some orthostatic intolerance issues before such as occasional dizziness upon standing but symptoms have become much more marked since ME onset, perhaps specifically starting some months after ME onset).

    To what extent do orthostatic intolerance issues (and resulting low oxygen to the brain) account for ME symptoms?

    Does joint hypermobility as measured by the Beighton scale (with/without other possibly related conditions such as stretch marks, varicose veins and prolapsed uterus) predispose someone with ME to have orthostatic intolerance, or to have worse orthostatic intolerance? (What is the mechanism that Dr Chris O'Callaghan thinks might be causing the relationship between migraine and hypermobility?)

    Retrospective questionnaires might be useful. But I'd really love to see a study a bit like the Dubbo study where people turning up at several doctor's clinics with an infection thought to trigger ME are tracked. At the acute illness onset, 1. hypermobility, 2. orthostatic intolerance and 3. presence and severity of acute illness and ME symptoms could all be measured with followup measurements say quarterly for up to five years for those patients who develop ME.
     
  17. Lisette

    Lisette Frida For All

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    Hi,

    " If you are not double jointed or hyper-extendy then I cannot see how you can be described as having hypermobility or EDS3, Lisette. "

    My doctors at the time considered that I might have EDS, because they were trying to figure out why my joints were getting increasingly unstable. But because I didn't have the easily classifiable signs, they didn't go any further with this idea.

    I don't have a wide range of motion. I have joint laxity, instability and inflammation. I have rackety crackling popping in all of my joints. A crude analogy-- I'm sort of like a steering wheel with a normal range of circular motion, but the whole wheel goes lopsided on the steering column and then gets stuck that way.

    So what interested me about this post is the idea that a person can have something affect their joint laxity right before the time that they were diagnosed with CFS/FM when they did not have a congenital condition to start with.

    My instability was not a result of weak muscles from deconditioning after getting CFS.

    I also developed POTS in the first year of CFS.

    I have many of the symptoms listed above in the post by Justy, other than joint issues.

    I am curious to know if a widespread weakened collagen/ connective tissue is more vulnerable to infection, or if an infection results in weakened collagen.

    Either way, this condition is chronic and painful, and I imagine changes some things in the functioning of the brain as a result. That's what interests me, and with the number of people with ME talking about it, it also seems significant.
     
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  18. JamBob

    JamBob Senior Member

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    Is hypermobility always a bad thing (ie. does the bendiness turn into something bad) or is it safe to ignore?

    My mum is extremely bendy and can do all kinds of odd party tricks even though she's never stretched or done any kind of yoga in her life.

    She also has skin issues (keloid scarring, bad wound healing for minor cuts or insect bites), Raynaud's, rosacea and random joint pain and inflammation (in her bigger joints) that lasts for months. Also autoimmune thyroid disease.

    She's the kind of person who won't consult a doctor unless she is dying. Apart from the painful joints - she doesn't complain of feeling sick in any way.
     
  19. Sushi

    Sushi Senior Member Albuquerque

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    From my personal experience of being "bendy and doing party tricks" earlier in life, it can lead to problems later. I now need to see an osteopath regularly to be "put back in place" and to do core strengthening exercises to make up for instabilities.
     
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  20. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    The vast majority of people who are hypermobile never have any problems as far as we know. If they did, rheumatologists would see masses of them and I never saw more than a handful of people in my career who seemed to have problems because of joint laxity. The problem is that nobody really knows. There are no proper studies. But from the people who come to clinics it looks as if most have no trouble.

    The people who do seem to get trouble are ballet dancers, many of whom are good at dancing because they are hypermobile. But even then, you probably get injuries if you are non-hypermobile ballet dancer.

    I think it is safe to ignore hypermobility in the sense that there is no reason to think we can do anything about it.
     
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