History and Metabolic Context

Ehlers Danlos Syndrome is a group of disorders of connective tissue that was formally identified in 1899 by Danish physician Edward Ehlers. Ehlers described patients that had characteristic symptoms including hyperflexible skin, lax joints and increased tendency of bruising. A few years later, Henri-Alexander Danlos, a French physician, published a paper describing similar symptoms. With the help of these two men, Ehlers-Danlos syndrome (EDS) became a formally recognized disease in the literature, although the cause of the new disease would not be understood for several decades (Parapia and Jackson, 2008).

While Ehlers and Danlos classified their syndrome as one single entity, Barabas (1967) identified that the disease has several different subtypes, with each displaying unique symptoms and clinical manifestations; this study notably identified several different forms of the disease, including the vascular form. There are currently six major subtypes of EDS, and all effect the synthesis or maintenance of collagen, a type of connective tissue. Collagen is the most abundant protein in the human body, and provides strength and structural integrity to nearly every cell; collagen is essential for the normal function of everything from bones and tendons to blood vessels. Although each subtype of EDS is surprisingly distinct, all patients share common symptoms including easily bruised skin and hyperflexible joints. All types of EDS are somewhat rare, affecting only 1:200,000 people (Malfait, 2010). The vascular type (vEDS), which is the most severe and has the highest mortality rate, is even more rare, affecting only a small percentage of EDS patients.

A landmark 1975 study identified that vascular EDS patients do not synthesize Type III collagen (Col3), and the authors showed that this lack of protein causes the symptoms identified nearly a century earlier by Ehlers and Danlos (Pope et al, 1975). The vascular type Ehlers Danlos Syndrome, previous called Type IV EDS, is extremely dangerous because it primarily affects collagen synthesis in blood vessels and abdominal organs. The inability to synthesize normal collagen makes these blood vessels and organs weak, and more susceptible to rupture, causing a potentially life-threatening hemorrhage.

With the dawn of the genetic revolution in the 1990s, some of the first mutations that cause vEDS were identified, and the disease was traced to the COL3A1 gene, which encodes Type III Collagen. Although initial studies hypothesized that Col3 was simply not produced, these newer experiments began to show that vEDS patients synthesize dysfunctional forms of Col3 (Smith et al, 1997). Only a year later, tests showed that vEDS mutations triggered the synthesis of smaller collagen precursors that were unable to form the triple-helix that is essential for Col3 stability and function (Superti-Furga et al, 1998). Over 300 mutations in this gene on chromosome 2q31 have since been documented, and all affect the production of collagen precursors that are vital to normal collagen function.

Together, these studies identified that the symptoms of vEDS were caused by the lack of functional collagen. Patients were simply not producing adequate Type III Collagen, and since collagen acts as a structural support for organs and blood vessels, these tissues were quite literally falling apart.

Type III Collagen obvious plays a crucial role in the body, and the COL3A1 gene, which is mutated in vEDS, encodes the precursors that form collagen. In a mechanism that is not well understood, three identical alpha-chains bind together and intertwine in a corkscrew-like shape to form one Col3 protein; individual precursor chains by themselves are nonfunctional. The Col3 homotrimer is functional, and can bind to other Col3 units, forming a long, flexible chain of collagen that is able to provide structural integrity and support to all the cells in the body.

Collagen Type III canonically plays a role in creating the extracellular matrix (ECM) of all cells, the small layer of support tissue seen in every organ and tissue in the body. Here, the protein’s role cannot be overstated, as the ECM surrounds nearly every cell in the body; although Col3 is present in the largest quantities in the intestines and arteries, it is also found in smaller amounts throughout the entire body. Col3 in the ECM provides structural support to the tissue and serves as an anchor, which prevents cells from moving and ensures consistent tissue organization (Smith et al 1997). Patients with vEDS lose this of structural support, which can be seen macroscopically with hyper-flexible joints and sunken facial features, as the collagen that normally supports these areas (i.e. various tendons and ligaments) is largely nonfunctional. The ECM is also vital to allowing the organ to perform its normal function; as but one example, the collagen in the ECM of the liver is required for proper detoxification and bile secretion, and to prevent liver fibrosis (Karsdal et al, 2015).

Col3 probably plays the largest role in major blood vessels, though, as it is a major component of arterial walls. These vessel walls need to be both elastic and extremely strong to accommodate the force of the contracting heart muscle. Interestingly, the very long collagen fibrils that can be seen microscopically in the walls are made up of both Col3 and Col1, and Col3 plays a major role in the development and organization of Col1. Col3 regulates the diameter of Col1 alpha-chains, which must be carefully controlled and kept uniform in order to ensure a symmetrical fiber; fibers that are too thin will be weak and overly flexible, and unable to perform their normal stabilization function (Liu et al, 1997). Correct fiber length is essential because Col1 is a major component in the walls of the aorta, the largest blood vessel in the body. Unsurprisingly, vEDS, which causes a deficiency in Col3, and thus causes downstream disregulation of Col1, increases the risk of aortic rupture, which is almost always fatal; both Col1 and 3 are essential to maintain the strength and elasticity of the aorta, as well as other major vessels in the body, like the femoral and carotid arteries (Vouyouka et al, 1999). Collagen does not play a major role in veins or smaller arteries, and these vessels are therefore not at increased risk of rupturing.

Beyond this structural role in the walls of arteries, Col3 also plays a major role in the healing process of skin, tendons, and bone. It is known, for example, that Col3 promotes regeneration of skin after a laceration, and inhibits the formation of scars by promoting the differentiation of myofibroblasts, which prevent scarring (Volk et al, 2011). In tendons and ligaments, Col3 is also able to increase healing by working to form small cross-links between broken cartilage fibers, which helps stabilize the repair site, thus speeding the healing process performed by other support cells (Liu et al, 1995). After bone breakage, collagen also plays a role in stimulating osteoblast activity, which secrete the organic material that is later mineralized into bone (Miedel et al, 2015).

 

Symptoms

aorta
Both left and right sides show the aorta, which has burst open due to a weakness in the vessel’s wall. (Source: Google scholar).

 

Vascular rupture– Greatly increased propensity for arterial rupture. The collagen that normally supports and strengthens the walls of the vessels is not present, so these blood vessels are highly susceptible to breakage. Such breakage can be preceded by aneurysm, fistula, or dissection, which are irregularities and structural weaknesses in the wall of the vessel. Breakage of large blood vessels, like the aorta or carotid artery can cause massive internal hemorrhage, which is almost always deadly.

Organ rupture– Organs, notably the small and large intestines and uterus, are particular vulnerable to rupture, as these organs use large amounts of Col3 to maintain both elasticity and strength. In vEDS, such collagen is not present, so the organs are not as robust and strong, and thus are prone to physically bursting (Germain and Herrera-Guzman 2004). The rupture of an organ is a life-threatening emergency, as various materials (i.e. enzymes, acid, partially digested food) can leak out into the peritoneal cavity, causing destruction of neighboring tissues and massive infection. Organ rupture can occur in vEDS patients from a relatively small amount of force, so patients are generally advised to avoid contact supports and heavy exercise. During pregnancy, uterine rupture is somewhat common, especially during the final trimester as the large baby places enormous pressure on the mother’s organs and surrounding blood vessels.

Facial dysmorphia– Various symptoms including thin, pursed lips, lobe-less ears, pinched nose, and prominent eyes are some of the most obvious features of patients with vEDS. Such features can be useful for diagnostic purposes, but are not always present and are not exclusive to the disease.

Hyperextension of joints– Collagen normally is a component of cartilage, tendons, and ligaments, which all prevent the hyperextension and hyperflexion of joints, most notably the wrists, fingers, and knees. Since collagen levels are so low, the tendons and ligaments may become weakened or physically damaged, allowing the joints to move more freely beyond their normal range of motion, which can cause irreversible joint damage.

Decreased bone mass—Bone volume and density are reduced in vEDS patients, which is associated with weaker bones that are more “brittle,” and thus easily damaged and broken. Although it was always believed that collagen is not present in mature trabecular bones (bones in the arm and leg), it was recently shown that Col3 does play an important role in strengthening the bone. Those without Col3 have bones with less mineralization and fewer bone precursor cells (Volk, 2014).

Thin skin– the skin appears much thinner than normal and is somewhat translucent, allowing veins to be easily seen on the skin of the patient, especially on the thorax and shoulders. Skin also appears abnormally aged and wrinkled based on the expected skin characteristics for the patient’s true age (Germain and Herrera-Guzman, 2004).

Increased bruising– Patients with vEDS bruise easily and frequently. Since blood vessels are fragile and at risk of breakage, bruising occurs very easily, even from relatively minor injuries or insults. Such bruising is caused directly by the weaknesses in the vessels, rather than by clotting or platelet disorders (De Paepe and Malfait, 2004).

The rupture of organs and blood vessels is obviously associated with a high mortality rate, although the other symptoms of the disease are relatively mild, allowing vEDS patients to live a relatively normal and active life. Unfortunately, symptoms tend to worsen with time, as the aging body is unable to fully repair itself; the body of a younger patient is remarkably resilient and adaptive, and is usually able to function normally, even without normal collagen levels. Correspondingly, one study showed that 25% of patients will experience one major complication of the disease by age 20 (i.e. arterial, bowel, or other organ rupture) and 80% will have one complication by age 40; many of these complications are fatal, resulting in the decrease life expectancy seen in vEDS patients (Pepin et al, 2000).

A self-made infographic that provides all of the pertinent information about the symptoms and treatment for vascular Ehlers Danlos syndrome. The infographic is meant to contain the most important information and be readable by any patient. (Images of collagen and child obtained from Google Images).

 

Diagnosis

Diagnosing vEDS can be particularly challenging due to the rarity of the disease. Few doctors are actively looking for, or even aware of, the vascular form of this disease. With the exception of organ or arterial rupture, most patients do not have severe enough symptoms to seek medical attention, and consequently many diagnoses are made post-mortem, after a vessel or organ ruptures. Vascular abnormalities tend to be found accidentally, such as during a routine ultrasound or from a CT scan in response to a medical problem not caused by vEDS; vascular weaknesses can generally be identified by an astute physician via MRI, CT, or ultrasound. Since collagen is generally not found in the blood and urine, these frequently used tests would not show the presence of vEDS. Anatomical abnormalities in the face, like a very thin nose, lobe-less ears and bulging eyes, may help alert a physician to the presence of vEDS, but these signs are not always extremely obvious.

The only definitive way to diagnose vEDS is to use genetic testing. Gene sequencing of the COL3A1 gene is required, and this can be compared to the normal sequence of Col3 available in online databases. Several hundred mutations that cause vEDS have already been reported in the literature, and a matching mutation in the literature would help confirm the diagnosis. Gene sequencing is rapidly becoming affordable, and this is the gold standard for diagnosis.

Collagen structure of vEDS patients can also be examined indirectly using SDS-Page gel electrophoresis, the method of choice before genetic testing was available. Mutant collagen has a different shape and molecular weight than normal collagen, which changes the speed in which the protein moves through the gel (Germain, 2007). While this does not necessarily indicate that the disease is vEDS, it can help to show abnormalities in collagen synthesis, which is caused by relatively few diseases, of which EDS is the most common. Today, though, this type of testing is less common, and is only used to confirm a mutation found via sequencing, or when showing that a newly discovered mutation in COL3A1 correlates with changes in collagen structure.

Recently, a new spectroscopic method was developed to determine the quality and quantity of collagen quality in bone that does not require gel electrophoresis. Bone with abnormal collagen has incorrect ratios of Carbon:Nitrogen, which can be detected using a newly discovered FT-Rama spectroscopy method (France et al, 2014). Although this method is not yet commonly being used in the clinic, it may serve as a useful tool to augment, rather than replace, existing diagnostic methods.

Ehlers Danlos Syndrome, Vascular Type

History and Metabolic Context

Disease Treatment

Conclusions and Proposals for Future Work

8 Replies to “History and Metabolic Context”

  1. Collagen type III also comprises the bulk of lymph node stroma. Do you know if patients with Ehlers-Danlos syndrome end up being immunocompromised to any degree?

    1. Hi Becca,

      Thanks for your comment, hope all is well! While I think that is a really interesting question, I wasn’t able to find any evidence of immunodeficiency in patients, as it seemed like the major symptoms occurred in the cardiac and musculoskeletal systems. It does seem logical that lymph nodes that rely on Col3 would be structurally weakened due to vEDS, but this may not necessarily directly correlate to immunodeficiency. Both Type I and II Collagen are also in the lymph node, so it seems possible that these other forms of collagen are able to provide enough structural support that the lymph node is not drastically affected.
      I did some additional research, though, and found that other types of Ehlers Danlos syndrome can present with immune system problems, most notably EDS Type VII. This disease affects Type I Collagen; this differs from vEDS, which mainly affects Col3, although vEDS can have some downstream effects on Col1. EDS VII is exceedingly rare so there isn’t a lot of research on the structural or biochemical causes for this immunodeficiency, except some studies mention that it always seems to present as periodontitis. Similar to vEDS, these patients also present with a variety of other symptoms, including easy bruising and skin hyperextensibility.

      If you want more information specifically about EDS VII, this is a useful summary from Nature: http://www.nature.com/ejhg/journal/v21/n2/full/ejhg2012132a.html

  2. Hi Mike! Awesome job with your webpages! You really made the information digestible and understandable for people who didn’t have any previous knowledge of vEDS. I just have a few questions (I read all of your webpages but decided to just leave one comment that pertains to all of them):
    1. You stated that on average people live until they are 51. Is that because over time people have had multiple bleeding instances that have had an additive effect of some kind? Or is it that people still die from one arterial or organ bleed that just happens to occur later in life?
    2. How quickly does collagen turn over in the body? Would organ transplant be a viable option for people who have an organ bleeds with vEDS or would the collagen in the new organ just get degraded? In terms of the new therapy proposal for artificial collagen, would that need to be administered frequently or would it be more long term like a joint replacement? Would that be added surgically? How would doctors decide which areas to apply the artificial collagen to if they have many susceptible areas? It doesn’t seem viable to continually go in and fix the bleeds with collagen if they are happening frequently, but it also doesn’t seem feasible to wrap every vessel in artificial collagen.
    3. Are women with vEDS more prone to miscarriages than other women? You stated that childbirth can be an issue for them, but is that pertaining to the pregnancy or the actual delivery of the baby? Are women with vEDS candidates for hysterectomies if they are prone to bleeds in their uterus?
    4. What happens to the untrimerized alpha chains that don’t trimerize to form COLIII? Are they degraded or do they aggregate and cause problems elsewhere in the body?
    5. You explained that there are several tools that are useable for diagnosing vEDS, but that there are still people who are not diagnosed until vEDS has killed them. How would you recommend remedying this? It doesn’t seem like vEDS impacts enough people to warrant universal screening of the population, but how else do we identify vEDS patients in time for them to get treatment?
    Thanks! 🙂

    1. Hi Kelly,
      Those are interesting questions.

      1. The average age is 51 because the vast majority of patients do not experience symptoms when they are younger. Although the collagen is mutated from birth, the bodies of pediatric patients are remarkably strong and resilient, and thus are able to function as normal without only minimal collagen synthesis. There is probably enough normal Col3 being produced that no symptoms are observed, and the body is able to repair and regenerate any minor problems in the collagen. Pediatric patients are also just smaller, so they simply need less collagen than an adult to function normally. Because of this, only 25% of patients will experience one major complication (organ or vessel rupture) by age 20, while a worrisome 80% will have one complication by age 40. As the body gets older, vessels and organs become less elastic and less flexible, and more likely to burst; the lack of collagen only makes this worse. In addition, with proper treatment, the body of a pediatric patients is simply better at dealing with a major blood loss or infection, while the adult body is simply unable to adapt; major surgeries to repair these damages are also much more risky in adults, increasing the death rate. With age, the body is simply no longer able to repair itself as quickly or effectively, resulting in decreased life expectancy.

      2. A. Collagen itself has a huge lifespan, and some studies predict that it can last well over 100 years (1). While collagen that is damaged or deformed is quickly replaced, the overall turnover rate is small. Thus, organ transplantation, in theory, seems like a good idea because the new organ with the collagen should be functional for a long time. The problem is that physicians don’t know which organ will burst, if it will burst, or when it will burst. With organs in such short supply, it would be irresponsible to simply replace an organ that “might” burst sometime in the future. Both the small and large intestines would need to be replaced, and other abdominal and reproductive organs are also at increased risk of rupture. In addition, organ transplants generally do not last forever, and these patients would likely need another transplant later in life, using even more organs. Thankfully, it is quite possible to repair a perforated organ, as this is not uncommon, especially in the elderly. Especially since surgery is so dangerous for these patients, it is generally preferable to simply wait until there are signs that the organ is significantly weakened and about to burst (i.e. a hernia) or an actual rupture occurs, which is usually not deadly with prompt treatment.

        I wasn’t able to find much information about the actual lifespan of artificial collagen, but I would hypothesize that it is not as long lasting as normal collagen produced by the body. While I don’t think the synthetic collagen would need to be replaced very frequently, it would likely need to be replaced a few times during the patient’s lifespan, just like an artificial joint. Artificial collagen would probably be most useful to support the major blood vessels (aorta, femoral artery, carotid), as a rupture in these vessels (but not digestive organs) is almost always fatal. As an FYI, there aren’t any small “bleeds”—these patients experience massive hemorrhages if a vessel bursts, and an organ rupture similarly sends blood and partially digested food flooding into the abdominal cavity, potentially leading to equally deadly infections. Organ perforations, though, can usually be fixed, while vessel perforations generally are rapidly fatal; it thus makes the most sense to put collagen on the blood vessels, rather than the organs. These collagen fibers would likely be added surgically, although there are currently no studies in humans to show if, or how, this would be possible.

      3. There is no data that shows vEDS patients are more susceptible to miscarriages. There is plenty of evidence, though, that shows that they are at much higher risk of vessel and uterine perforation, both in the later stages of pregnancy (third trimester) and during birth (2). There is massive pressure on the uterus due to the sheer size of the baby, and since this organ is also dependent on Col3 for strength and flexibility, it is damaged during many pregnancies. For this reason, many babies are delivered preterm and/or via C-section. Uterine rupture can really occur during at any time of the pregnancy, though, and rupture would likely result in emergency surgery to remove the baby and fix the injury to the mother. Since any type of surgery carries an increased risk of fatality for vEDS patients, unnecessary surgeries are generally not used, so it seems unlikely that hysterectomies are used frequently.

      4. The body has several different methods to breakdown and recycle collagen. I didn’t find any evidence that collagen accumulates and causes further problems for vEDS, so these breakdown methods must be effective. Interestingly, one of the future treatments for vEDS involves doxycycline, which actually slows the collagen degradation process (More information on Conclusions page). Although this has only been tested in mice, no major side effects were reported, leading me to believe that collagen does not cause major problems, even if it accumulates.

      5. I think it is really difficult to increase diagnostic rates among the general population simply because it is such a rare disease. It doesn’t really make sense to screen the entire population, as this would be extremely costly and provide little benefit. As genetic sequencing becomes more and more prevalent, and likely a major part of our future healthcare system, it will be significantly easier to diagnose all patients, as a computer will simply be able to read a genome and find mutations in a patient that has undiagnosed vEDS. Luckily, most patients with vEDS inherit it from their parents, making diagnosis much easier, as physicians are aware of the condition and can diagnose it at birth. While early diagnosis is obviously nice, the treatment options are currently very poor, and an early diagnosis is not necessarily going to make a difference in the prognosis of the patient. Celiprolol has had some effect on decreasing the rate of vascular rupture, but much of vEDS treatment occurs after a vascular or organ rupture, where the diagnosis, or the lack there of, is largely irrelevant.

      1: http://scholarcommons.sc.edu/cgi/viewcontent.cgi?article=1143&context=chem_facpub

      2:http://www.nature.com/gim/journal/v16/n12/abs/gim201453a.html

  3. Hey Mike, great analysis and summary of a pretty interesting disease. I read your description of the symptoms, but I wasn’t exactly sure how prominent these symptoms would be. For example, the facial dysmorphias, joint laxity, increased bruising, and thin skin – are these quite noticeable in patients with vEDS (with at least moderate severity of the disease)? I mainly ask this because, after reading this page and the Treatment page, it seems that rupture of the arteries is (a) very dangerous and potentially fatal, (b) tricky to treat surgically, and (c) even more dangerous to treat surgery, given the nature of this disease. And so I ask this question about the prominence of these symptoms because early diagnosis of vEDS may be the only way to save these patients’ lives. In addition, are there objective ways you know of to measure bone mass, facial dysmorphia, and joint extension, that is not overly-invasive? Again, in the hopes of forming the diagnosis earlier. Thanks!

    1. Hi Besher,

      Thanks for your comments! If you take a look at the infographic I made, you can see a picture of a young girl who has some of the physical characteristics of vEDS. The changes to facial structure, like prominent eyes and very thin lips are only visible if you look closely, and these facial features are not unique to vEDS, as they can be seen both in other diseases and in healthy patients. Thus, while they can be seen, they aren’t necessarily going to be noticed by a physician that is unfamiliar with the disease.
      The other symptoms like joint laxity and easy bruising are definitely noticeable by the patient, but aren’t necessarily something they would report to their physician. Many people bruise easily or can hyperextend their joints, so this wouldn’t necessarily be a major cause for concern even if the physician were aware of the disease. Patients definitely have extremely lax joints though, and can bend them far past their normal stopping point; for example, a patient could stretch their finger very far back toward the wrist, without feeling pain.

      You are definitely right that early diagnosis is useful, and hopefully the physician would recognize the group of symptoms as a cause for concern, and further investigate the matter. As for diagnosis, a physician could get a good idea of joint flexibility by simply bending the fingers, wrists, and knees, as it will be quite obvious that these patients have a drastically increase range of motion (as simply measured by angles of maximum flexion and extension) due to the lack of collagen support in the ligaments that normally stop hyperextension. Changes to bone density can sometimes be seen on a normal X-Ray, although can be specifically measured via a DXA scan. The DXA also uses X-Rays to measure how much radiation is absorbed by bone, with particularly thin or weak bones absorbing less radiation that strong bones. Finally, there are a variety of ways to measure facial dysmorphias, as the average length between any two points on the face is well documented and recorded. The physician can take these measurements with a ruler and then compare them to know values to roughly quantify changes in facial structure.

      Here is some more information about the BXA scan (http://www.oif.org/site/DocServer/Bone_Mineral_Density.pdf?docID=7185) and the facial measurements (https://www.peds.ufl.edu/divisions/genetics/teaching/facial_dysmorphology.htm) if you want to learn more.

  4. Good evening Mr. Chase,

    I think you did a fantastic job on this page. No insult to anyone else, but this is the most well organized site I have been on. I’m going to take a look on your other pages and comment elsewhere. The only thing I wanted to point out here is an inconsistency on your self-generated image at the bottom of the page. the ‘Cause of Disease’ section has no bullet points whereas the other blurbs do. I don’t know if this was intentional, but if it was a mistake I wanted to draw it to your attention.

    also, please add hyperlinks to your other pages at the bottom of this one.

    1. Hi Ryan,

      Thank you so much! I really tried to make the pages very organized, because I know that always helps me when I am trying to read through a lot of new information.

      Also thanks for letting me know about those problems, I fixed them!

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