Funded Research


Clinical Research Major Grants 2020

How do muscles and tendons influence metabolic cost and exercise tolerance in hypermobile Ehlers-Danlos Syndrome?

Chronic pain and fatigue/exercise intolerance is a major complaint in individuals living with hypermobile EDS (hEDS) and may have a severe impact on quality of life and activities of daily living. Despite this huge clinical problem, it is currently not known how or why these symptoms may arise or how they can be treated effectively. Most subtypes of EDS are caused by alterations in collagen structure. Collagen is a major component of tendons, connecting muscles to bones to cause movement of our joints. Lower limb tendon stiffness is reduced in EDS, which we hypothesize is the reason for reported feelings of pain and fatigue during walking in these individuals. Importantly, there is a widespread notion that exercise for these individuals should generally be avoided, due to the fear of joint dislocations, and increased extensibility of the tendons; however, evidence for this statement is lacking. Therefore, we aim to test this hypothesis by:
1. Assessing lower limb tendon stiffness in individuals with hEDS using real-time ultrasound imaging of
muscles and tendons during walking.
2. Evaluating the feasibility and effectiveness of an exercise intervention aimed at increasing tendon stiffness.
3. Quantifying the impact of altered muscle-tendon function in hEDS individuals on the energy cost of muscle contraction, muscle pain and fatigue to better inform clinical rehabilitation practices. There is a need for better understanding the impact of hEDS on activities of daily living, including walking, an easy and accessible mode of exercise for individuals with hEDS. A clearer understanding of the mechanisms of subjective fatigue, exercise tolerance and energy expenditure is needed. This investigation proposes to compare muscle-tendon properties of hEDS and healthy-controls and evaluate the impact of these properties on energy expenditure, subjective pain, fatigue and exercise (in)tolerance. We further propose to investigate the impact of exercise training on these properties. This information will help to inform treatment plans for individuals living with hEDS to reduce fatigue, safely engage in physical activity and improve their quality of life.

Primary Investigator:
Dr. Jared R Fletcher
Mount Royal University
4825 Mt Royal Gate SW,
Calgary, AB
T3E 6K6,

Headache disorders and craniocervical junction abnormalities in hypermobile Ehlers-Danlos Syndrome

People with hypermobile Ehlers-Danlos Syndrome (hEDS) frequently suffer from headaches, neck pain and other neurological symptoms. However, the cause of these symptoms is poorly understood. Hypermobility of the craniocervical junction (joints between the skull and top of the spine) has been proposed as a major cause of these symptoms by causing pressure or stretch related injury to the brainstem, nerves and blood vessels in the neck. This has been termed the cervicomedullary syndrome (CMS). Reports in small numbers of people with hEDS have suggested that craniocervical fusion surgery may stabilise the cervical spine and thereby dramatically improve headache and quality of life. This has not been studied in formal trials, and the rationale for surgical treatment is not widely accepted. It is difficult to decide which (if any) people with hEDS may benefit from surgery as the symptoms of CMS have other potential causes, including migraine. The radiological measurements used in the assessment of CMS are obtained from upright dynamic magnetic resonance imaging (MRI). However, these measurements were not originally developed to be used in this condition, and we do not know the normal ranges for these values on upright MRI.
We will systematically study headache disorders, neurological symptoms and signs in 200 people with hEDS. We will do this using structured clinical interview, physical examination, and completion of questionnaires of pain-related disability, quality of life, autonomic symptoms and affective scores. We will perform an upright dynamic MRI in three equal groups of 40 participants (120 in total): (1) Healthy controls without joint hypermobility or symptoms of CMS; (2) People with hEDS but no symptoms of CMS; and (3) People with hEDS and symptoms of CMS. We will record the presence of craniocervical junction abnormalities and radiological measurements of hypermobility.
In additional studies, we will look for evidence of brainstem tissue damage in people with hEDS who have symptoms suggesting CMS and radiology suggesting craniocervical hypermobility, using specialist imaging of brainstem pathways and electrical tests of brainstem function.
We anticipate that describing the burden of headache disorders and neurological symptoms in hEDS will increase awareness of these symptoms to healthcare providers, and better inform appropriate investigation and management. We will be the first group to establish normative ranges for the assessment of the craniocervical junction on upright dynamic MRI. We will be able to show to what degree this region of the body differs in people with hEDS compared to healthy controls. By comparing people with hEDS with and without symptoms of CMS we can study which imaging abnormalities are most related to symptoms. The main hypothesis of this study is that craniocervical hypermobility in patients with hEDS would cause structural brainstem or spinal cord damage. If our results were in line with this hypothesis, then we would provide evidence supporting larger surgical trials that will help to deliver improved care to highly disabled patients. Alternatively, we would provide data against potentially unnecessary invasive and expensive neurosurgical treatment.

$149 698.13
Primary Investigators:
Dr. Manjit Matharu
University College London (UCL) Queen Square Institute of Neurology
Queen Square,
London, WC1N 3BG 
United Kingdom

Health & Social $300k Grant

Oral manifestations in the Ehlers-Danlos Syndromes

Information is sparse with regard to oral health of patients affected by Ehlers-Danlos syndromes (EDS). Systematic clinical oral investigations are missing for most of the 14 EDS types, and if available, study cohorts were small due to the rarity of the syndromes. The lack of evidence has led to various incorrect assumptions. For example it is repeatedly claimed that vascular (and classical) EDS are associated with a high risk for periodontitis. This statement is based on a single case report with a high risk of bias and it is more likely that this assumption is incorrect but systematic clinical investigations on periodontal manifestations in representative patient cohorts are missing. Another example are dental implants, for which few adverse side effects were anticipated. This might be true for some EDS types, but in a recent case series of individuals with periodontal EDS, we observed rapid progressing bone loss around implants leading to implant loss after a few years. These incorrect assumptions may lead to diagnostic errors and faulty treatment in patients affected with EDS. Various other dental and oral anomalies have been described in case reports / series and narrative reviews, which could have clinical diagnostic value if the prevalence and specificity in the different EDS types would be clarified. As members of the International Consortium on Ehlers-Danlos Syndromes and Related Disorders and through international collaboration we have access to large cohorts of patients with different EDS types. We aim to recruit at least 50 individuals per EDS type for clinical dental investigations in six European centers. This seems realistic for hypermobile EDS, classical EDS, vascular EDS and periodontal EDS. Based on clinical studies we will assess oral health in people with different EDS types and develop and disseminate oral treatment strategies. Finally, patient leaflets and fact sheets for dental professionals will be designed, which will have an immediate impact on oral health related quality of life of EDS patients.

Primary Investigator:
Dr. Ines Kapferer-Seebacher
Medical University of Innsbruck
Christoph-Probst-Platz 1,
Innrain 52 A, 6020 Innsbruck 

Investigating the relationships between functional magnetic resonance imaging, subjective and objective clinical findings in the upper cervical spine in people with hypermobility-related disorders

Symptoms such as headache, neck pain, nerve pain in the arms and legs, and disturbances of heart rate and
blood pressure, thought to be derived from the upper cervical spine (upper neck) and craniocervical junction (the junction of the neck with the base of the skull) can be frightening and debilitating. It is suggested that these symptoms can result from instability of these joints and subsequent pressure on the spinal cord and nerve roots as they pass from the cord out to the body. Clinically, both from physical examination and from radiological imaging, it is difficult to establish if this is truly the case. Whilst upright dynamic magnetic resonance imaging (MRI) is used to investigate such symptoms, there is a lack of evidence as to which measurements on MRI, if any, are truly linked to the presenting symptoms. It is also not clear if any of these measurements are commonly found in hypermobile people without symptoms. If the latter is true, then the MRI results could be unhelpful or misleading for people with symptoms. It is also not clear which tests and measures taken in clinic by doctors and physiotherapists are most useful to help guide decisions on how to help people manage th2ir symptoms. Nor is it known if or how these clinical
tests and measures relate to MRI findings. This study aims to answer these questions by comparing upright dynamic MRI of the cervical spine and craniocervical junction in two groups of people with confirmed generalised joint hypermobility. The first group is those who have symptoms that could be coming from the upper cervical spine. The second group is those with hypermobility who do not have neck problems. Everyone in both groups will be asked a series of questions, and will undergo a clinical examination for head and neck, and shoulder and arm concerns that might arise. The study will use current accepted standards of clinical assessment and validated questionnaires. The usefulness of two new questionnaires will also be assessed. The MRI and clinical results from the two groups will be compared. Statistical techniques will be used to determine if MRI and/or clinical signs consistently identify people with neck symptoms compared to those without. Clinicians around the world can use this information in their clinics to help guide their practice, helping to improve the experience of people with these truly awful symptoms.

Primary Investigator:
Dr. Ann McCarthy
Central Health Physiotherapy
53-64 Chancery Ln,
Holborn, London WC2A 1QS,
United Kingdom

Spring Microgrants 2020

Pain trajectory and exercise-induced pain flares during 16 weeks of strength training in individuals with hypermobility spectrum disorder and shoulder complaints for more than three months

Hypermobility Spectrum Disorder (HSD) is a recently defined group of conditions related to the symptomatic manifestation of Generalized Joint Hypermobility (GJH), and is characterized among others by symptoms in the shoulder joint including and not limited to shoulder strength deficits, shoulder instability and shoulder pain. This condition has negative consequences in daily living for these people, but currently there is no optimal treatment for this population. In an ongoing randomised controlled trial (RCT) ( identifier NCT03869307), we are investigating the effectiveness of a 16-week heavy strengthening exercise programme in people with HSD and persistent shoulder complaints/problems. This study will use data collected in the RCT to obtain knowledge about associations between pain trajectories, exercise-induced pain flares and exercised load in this population. In an exercise diary, the participantss report pain before and after each exercise session, which makes it possible to analyse if pain decreases, increases, stays the same, and how it varies during the strengthening exercise programme. In addition, associations between pain and the applied load in the specific exercise session will be studied. This information may guide healthcare professionals responsible for effective and safe treatment, in predicting response to heavy strength training, and inform a deeper understanding of possible pain patterns during exercise for this population. This study is under the supervision of Associate Professor Dr. Birgit Juul-Kristensen, University of Southern Denmark, Odense, Denmark. The funding will cover salary for a research assistant, who will type in all data from the exercise diaries (approximately 100 participants) and help with the data analysis.

Primary Investigator:
Mr. Behnam Liaghat
Syddansk Universitet(University af Southern Denmark]
Campusvej 55
5230 Odense M

Understanding shoulder problems in patients with Ehlers–Danlos Syndrome hypermobile type and Hypermobility Spectrum Disorder: a cross-sectional study.

Patients with hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD)typically present with hypermobility in most of the joints, which is frequently associated with recurrent joint dislocations[1-3]. Some important mechanisms that are thought to play a role in shoulder dislocation are the ability to sense the shoulder joint, muscle function, and movement of the shoulder blade during arm movements.
The ability to sense the shoulder joint plays an important role in maintenance of joint control during all arm movements [4-6], which may lead to severe shoulder complaints if left undiscovered. Poor shoulder position sense has been reported in adults with recurrent anterior shoulder instability [7], but not in adolescent swimmers with hypermobility [8]. One study has investigated dynamic shoulder-position sense without finding any significant deficits in patients with hEDS using advanced measurement methods [9, 10], while several previous studies have consistently reported deficits of dynamic knee-position sense in this patient group compared with healthy people [11, 12]. Feasible dynamic methods for clinical use, e.g. active joint reposition[13], which measures the ability to re-position the shoulder to a previous position, have shown deficits in patients with anterior shoulder instability[14], but this method has not yet been used in patients with HSD or hEDS. Abnormal movement of the shoulder blade has been found in patients with shoulder instability and dislocations[15]. Less upward rotation and more inward rotation of the shoulder blade, which are indicative of poor movement, have consistently been reported in patients with multidirectional instability during arm elevation[16-21], which may compromise arm movements and impair shoulder control[19-22]. Also, al3ered muscle activity has been found in patients with shoulder laxity, adolescent swimmers with hypermobility, and adults with MDI multidirectional instability [23-25].
While there is limited and inconclusive research on joint-position sense, no studies have, to our knowledge, simultaneously investigated joint-position sense, movements of the shoulder blade and muscle activity of the shoulder in patients with hEDS/HSD. Investigation of these parameters during functional movements, such as shoulder elevation in different directions with and without resistance will provide useful understanding of shoulder complaints in patients with hEDS or HSD. This knowledge will provide the basis for further investigating the effect of more specific exercise-based treatments targeting these shoulder deficits in this patient group. The aim of this study is to investigate shoulder reposition sense, movements of the shoulder blade, and muscle activity pattern in patients with hEDS or HSD with shoulder complaints such as persistent pain or instability  compared to healthy controls using standardized feasible procedures.
This cross-sectional study is an international collaboration conducted by Behnam Liaghat, PhD Fellow at the University of Southern Denmark, Odense, Denmark, under the supervision of Associate Professor Dr. Birgit Juul-Kristensen, University of Southern Denmark, Odense, Denmark, and will be conducted in collaboration with Professor Dr. Shea Palmer, University of the West of England, Bristol, United Kingdom. The funding will cover travel expenses for the researchers and the included participants.

Primary Investigator:
Mr. Behnam Liaghat
Syddansk Universitet(University af Southern Denmark]
Campusvej 55
5230 Odense M

Do patients with Ehlers-Danlos syndrome have early-onset osteoarthritis?

Osteoarthritis or joint wear is the deterioration in quality of one or more joints. A joint is the place where two bones meet and move relative to each other. For smooth and pain-free movement, the ends of the bones fit together: one end usually has a rounded shape, the other a flat or hollowed-out shape. On the surface, the joint is covered with a layer of cartilage, surrounded by a case, called the joint capsule. The joint capsule produces a gelatinous fluid that feeds the cartilage. In osteoarthritis, this structure is irreversibly damaged: the cartilage dries out and becomes crumbly. This makes the cartilage layer thinner, more rough and less resilient. Sometimes pieces come loose, leading to the sensation of joint blockages. In addition, friction between these rougher joint surfaces and the capsule can also cause inflammation and pain (Figure). The two main features of osteoarthritis are pain and movement restriction. At the beginning, pain occurs when loading the joint, e.g. during sports or even when walking. In a more advanced stage, there is also pain at rest that can interfere with sleep. Joint stiffness can also occur. Two types of osteoarthritis can be distinguished. On the one hand, osteoarthritis can develop in a normal joint, due to aging. It usually starts from the age of 50 and is most common in the knees, hips and hands. This can happen to everyone. On the other hand, osteoarthritis can develop due to an illness or injury. This develops at a younger age, usually between the ages of 35 and 50, and is therefore called osteoarthritis at early-onset or premature osteoarthritis. It has been suggested that because of the hypermobility in the joints and the frequent dislocations ((sub)luxations) and sprains, patients with Ehlers-Danlos syndrome (EDS) are prone to develop early osteoarthritis. However, no studies have been published that determine whether patients with EDS actually have early osteoarthritis and how severe it is. It is important to investigate the occurrence of early-onset osteoarthritis in EDS patients because it can help to better understand the types of pain and pain mechanisms in EDS and because it can help to improve and specify the treatment of EDS patients regarding physiotherapy and pain medication. Therefore, we set up a research study to investigate with radiography (X-rays) whether patients with classical EDS, classical-like EDS and hypermobile EDS, between 35 and 50 years old, have early-onset osteoarthritis in the hands, knees and hips and whether this is different between these types of EDS and compared to healthy persons. Also mobility of the joints is measured to investigate whether there is a relationship between the degree of (hyper)mobility in a joint and the presence of early-onset osteoarthritis in that joint in EDS patients.
Currently, 31 EDS patients have been tested, but to have reliable results it is desirable to expand the patient group. Funding for this study will be used to pay the X-rays of newly enrolled EDS patients and to pay a statistician who will analyze the results.

Primary Investigator:
Dr. Lies Rombaut
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,

Assessment of the respiratory function in a mouse model of classic Ehlers-Danlos Syndrome

Diseases of the connective tissue, including Ehlers-Danlos disease (EDS), are systemic and negatively affect multiple tissues and organ/systems. In fact, although EDS is characterized by various skin features (including hyper-extensibility, fragility, softness, bruising, abnormal scarring) and joint hypermobility, it often causes joint and muscle pain in addition to a variety of other symptoms. These, including symptoms affecting the respiratory system, are less studied but can significantly reduce the quality of life of EDS patients. A few, sparse studies have reported an increased number of respiratory symptoms (wheezing, coughing, chest pain,breathing difficulties), lung diseases and even asthma in patients with EDS. However, data on the prevalence and/or incidence of these cases are not available and no in-depth studies on the respiratory system of EDS patients have been performed. We recently characterized the respiratory phenotype in a mouse model of recessive osteogenesis imperfecta (OI), a disease that causes severe bone fragility but also skin alterations, with some overlapping features with EDS. OI is most often caused by alterations in type I collagen, the most abundant protein in our body and an essential structural component of our connective tissues. Our study showed that type I collagen expressed in the lung tissue presents similar defects to those seen in bone and skin; moreover, we demonstrated that OI mice have both morphological and functional respiratory defects with important implications for patients with this disease. Indeed, previous theories suggested that the respiratory function is impaired because of the musculoskeletal issues caused by OI. Instead, our study indicated that collagen defects directly impact lung structure and function. Therefore, our working hypothesis is that collagen alterations such as those impacting type I collagen in OI or type V or III collagen in EDS also primarily affect the respiratory system with deleterious pathophysiologic consequences that could help explain the symptoms observed in these patients. We believe it is critical to begin to study these important aspects of the disease. We thus propose to utilize a well-described mouse model of classic EDS (carrying mutations in the Col5a1 gene) and determine potential alteration in its respiratory function and respiratory mechanics using the forced oscillation technique, a powerful tool permitting the experimental assessment of lung function in a comprehensive, detailed, precise and reproducible manner. Our pilot study provides an opportunity to explore these aspects in a mouse model with the ultimate goal to translate the new knowledge into improvements in the respiratory management and care of EDS patient.

Primary Investigator:
Dr. Roy Morello
University of Arkansas for Medical Sciences
4301 W Markham St,
Little Rock, AR 72205,
United States

Investigation of the EDS related selective binding mechanism between FKBP22 and collagens

Ehlers-Danlos syndrome (EDS) is an inherited connective tissue disorder with thirteen clinical subtypes mainly characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Mutations in a protein called FKBP22 cause kyphoscoliotic EDS (kEDS). Individuals with kEDS have a broad spectrum of phenotypes, such as the curved spine, excess joint flexibility, poor muscle tone, stretchy skin, hearing loss, and breakable aorta. The mechanism by which reduced or abnormal FKBP22 leads to kEDS is unknown and represents a critical gap in our knowledge. I have recently discovered that the FKBP22 protein binds to some of the 28 different collagens but not others. Understanding how and where FKBP22 differentially binds collagens has never been explored. Determining the nature of these interactions would contribute to a fundamental understanding of kEDS disease mechanisms and contribute to the development of novel therapeutic interventions.

Primary Investigator:
Dr. Yoshihiro Ishikawa
The Regents of the University of California, San Francisco
505 Parnassus Ave,
San Francisco, CA 94143,
United States

Validating the spider: a symptom profile tool for hypermobile patient groups

The spider: mapping your symptoms
Patients with joint hypermobility report joint pain as their main symptom. However, their lives are often affected by many other problems situated outside the muscles and joints as well. Fatigue, feeling unwell after exercise, feeling faint in an upright position, abdominal pain, slow bowel transit, diarrhoea, and urinary incontinence are examples of additional ‘non-musculoskeletal’ symptoms.
Since 2017, these bothersome symptoms have been acknowledged by the international EDS consortium and are referred to as the comorbidities of hypermobility. Unfortunately, when seeking treatment, many patients feel as if these symptoms are neglected at first, because they are not taken into consideration when diagnosing HSD and EDS. The reason is that diagnosis of EDS is based on the more structural symptoms, such as abnormal scarring and fragility of soft tissues. Although the functional symptoms do not have a central place in the diagnostic procedure, researchers found that they lower quality of life importantly. In fact, the impact of symptoms like fatigue, difficulty regulating blood pressure, and stomach and bowel problems is often as large as the impact of pain. Furthermore, evidence is growing that subgroups exist in patient with HSD and in hEDS, and that these may need different treatment strategies. For instance, a Dutch-Australian research team evaluated 101 children with hEDS/HSD and detected three subgroups. The most severely affected subgroup reported a larger number of non- musculoskeletal symptoms and were more likely to have a worse disease trajectory growing up. A similar finding was described in adults by Belgian researchers. To register the non-musculoskeletal symptoms (comorbidities) of joint hypermobility in a standardized way, the ‘Spider’ was developed. The end result of this questionnaire is a graph shaped as a spider web, that shows health care professionals which issues require further assessment and should be treated as a priority. For instance, if patients have severe digestive problems or symptoms related to blood pressure regulation, these should be addressed first before starting intensive physiotherapy or physical training. In addition, the spider can be used to track how a patient’s health is evolving over time and to monitor the effects of treatment.
Finally, researchers will also be able to use the spider, since it provides insight into the prevalence of non-musculoskeletal symptoms in HSD and EDS, and reveals whether differences exist between patient groups with HSD, hEDS and other EDS-types. In many countries, patients with EDS-diagnoses are more likely to receive acknowledgement, assistance and reimbursement for treatment than patients with HSD. The faulty assumption that hEDS is more severe than HSD could be confuted by symptom registration on a large scale. Because little is known about the genetic background of HSD and hEDS, the spider could be an interesting tool to shed light on the differences and similarities between both pathologies. Finally, the spider could be helpful to detect groups of similar patients within large populations with the same diagnosis. Researchers hope to understand whether patient subgroups with different symptoms also have a different genetic

Primary Investigator:
Miss Inge De Wandele
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,

In-depth three-dimensional study of dermal connective tissue ultrastructure in different Ehlers-Danlos Syndrome subtypes and Hypermobility Spectrum Disorders

For diagnosis and research it is very useful to be able to look at the skin of patients with Ehlers-Danlos syndrome and Hypermobility Spectrum Disorders using a transmission electron microscope. To be able to do this, a small sample of skin is processed and a very thin slice is taken and put in the microscope. Using this type of microscope, it is possible to look at a cross section through the cells and collagen of the dermis (skin layers) at very high magnification, to see if they are normal or not. By comparison, with a scanning electron microscope it is possible to see the surface of tissues at high magnification in three dimensions. Scanning electron microscopy gives interesting results, but for the study of the dermis, is less useful. Even when both of these types of microscope are used, it is still very difficult to tell what is happening in the skin in three dimensions. However, a microscope was recently developed where, in an automated fashion, slice after slice is taken from a biopsy and the cut surface is photographed after each slice has been taken. This makes it possible to build up a three-dimensional picture of the cells, collagen strands and elastic fibres. Using multiple slices and a computer to build up a three-dimensional image is called computer tomography which is what x-ray, CT and magnetic resonance imaging body scanners do – which is especially useful when looking at organs. However, when wishing to look at cells and collagen at the microscopic level, electron tomography is required. It is our expectation that by looking at skin biopsies from patients suffering with Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders using this new piece of equipment (Serial Block Face Scanning Electron Microscope) it will help scientists understand more about the molecular biology of these conditions. Only a few research institutions in the UK own these new microscopes. This grant application, in large part, is to pay for the services of one of these universities, with interpretation in large part being the job of those applying for this microgrant. The institution we have approached is the University of Manchester Wellcome centre of Cell-Matrix research.

Primary Investigator:
Mr. Bart Wagner
Sheffield Teaching Hospitals
Royal Hallamshire Hospital,
Glossop Rd, Broomhall,
Sheffield, S10 2JF 
United Kingdom

Zebrafish as a model to study pain in rare subtypes of Ehlers-Danlos syndrome

Chronic pain is present in the majority of patients suffering from Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) and is a major reason to seek medical help. It has a detrimental effect on the quality of life and psychosocial well-being of EDS/HSD patients. Despite its high prevalence, little is known about the precise origins and mechanisms contributing to EDS-related pain and the pain is usually inadequately controlled by currently used treatments. An important reason for this is the lack of studies investigating the mechanisms and pathways that initiate and maintain EDS-related pain. Animal models can give valuable insights into mechanisms and pathways that are affected in human disorders. Zebrafish has emerged as a promising animal model to reliably study pain-related behavior and associated mechanisms, since their nervous system shows great similarity to humans. Our group recently created zebrafish models for the rare spondylodysplastic EDS (spEDS) subtype due to defects in B4GALT7 and B3GALT6, and the musculocontractural EDS (mcEDS) subtype due to CHST14 mutations. Both subtypes are caused by defects in the biosynthesis of proteoglycans, which are important molecules providing structural support to connective tissues but are also involved in other biological functions, such as during development of the nervous system. Since clinical practice and some reports suggest that patients with spEDS and mcEDS suffer from chronic pain, we want to use these zebrafish models for our pain studies. A first step in the elucidation of the alterations in the pain pathways associated with these EDS subtypes is to assess whether the zebrafish models experience pain. Therefore, the general aim of this proposal is to document pain- and stress-related behavior in spEDS and mcEDS zebrafish. To obtain this information, the spontaneous free-swimming behavior of these zebrafish will be carefully monitored and analyzed. If pain-related behavior is observed, we will try to ameliorate the observed pain-related behavior by administering several types of pain medication to the water and check if th3s reverses the behavior. In addition, the spEDS and mcEDS zebrafish will be crossed with a specific reporter line allowing to visualize the nervous system. Alterations in neuronal development will be evaluated in this way. When successful, this proof-of-concept data will set the stage for further in depth analyses. This proposal is part of a large, ongoing and collaborative research line at the Center for Medical Genetics Ghent (Belgium), aiming to better understand the molecular and cellular pathways and mechanisms that contribute to pain in EDS, with the ultimate goal to identify targets for safer, more efficient and (potentially) disease-tailored approaches for pain relief.

Primary Investigator:
Dr. Delfien Syx
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,

Patients with hypermobility related disorders have a significant number of orthopaedic interventions on multiple sites and at a young age: data from a tertiary referral centre

Hypermobility is a common body type and it is estimated to affect 20% of the population . Only 10% of people with hypermobility are symptomatic which often causes a confusion regarding the nature of pain in these patients . Furthermore there is an anecdotal impression among some doctors that patient with rare forms of EDS , such as classical or vascular type , do not suffer with pain or significant musculoskeletal issues. Others believe that this is simply a presentation of fibromyalgia with oversensitivity to pain in anxious patients who happen to be hypermobile. We have observed an increase in the rate of orthopaedic surgical procedures undertaken in patients attending the hypermobility clinics compared to those attending the general rheumatology and chronic pain clinics. This indicates that mechanical pathology rather than pain oversensitivity plays an important role in their symptoms. We have performed a retrospective review of medical records of 350 patients attending a hypermobility clinic at our tertiary referral centre, University College London Hospital, between January 2018 and December 2018. We found that the mean age was 36 years , 37 % had EDS(hypermobile, classical, vascular or other rare type) with 13% had documented genetic mutations 83 patients (24%) had undergone orthopaedic interventions including 9 who had EDS with confirmed genetic mutations. 54% of patients who had surgical intervention were under the age of 40. The total number of surgical procedures in the cohort was 227 (equating to 0.6485 interventions per patient). Of those requiring operative intervention, the average number of interventions per patient was 2.73. One third of patients had surgery on two or more joint groups, including 8 patients (2%) who had surgery in four or more joint groups. Knees (24%) and hips (23%) were the most common sites for operative intervention with 9% having surgery on their shoulders. 29% of pts had significant hypermobility with a Beighton score of 7 and above but there was no correlation between Beighton score and number of surgical procedures. Only 2% of cases were referred from an orthopaedic team thereby excluding a referral bias. We have highlighted that patients with hypermobility related disorders have a significant number of orthopaedic surgical procedures on multiple sites and at a young age, with indication of mechanical pathology playing an important role in their symptoms. The Beighton score did not appear to be a reliable predictor of surgical intervention. This is not surprising given that the score only covers 5 joint areas and excludes common surgical sites such as the hips and shoulders. This study was accepted as an oral presentation at EULAR (the main European rheumatology meeting) in June 20202 and received a very good feedback We would like to apply to this grant to perform subgroup analysis and get a professional statistical advise to be able to publish this in one of the main rheumatology journals. We are aiming to complete this by June 2021

Primary Investigator:
Dr. Hanadi Kazkaz
University London Hospital
12 Queen Square, Holborn,
London, WC1N 3BG
United Kingdom

Assessing the effects of cardiovascular and isometric exercise in vascular Ehlers Danlos syndrome

Vascular Ehlers-Danlos (vEDS) is an inherited connective tissue disorder caused by a deficiency in type III collagen. Patients with this disorder have spontaneous rupture of blood vessels, often resulting in sudden death at a young age. The risk of rupture is difficult to monitor or predict and there are no treatments for prevention of rupture in vEDS. The issue of what type and how much exercise is safe for patients with vEDS is of high concern among patients who want to do whatever they can to prevent spontaneous rupture. The most conservative answer in terms of reducing stress on the blood vessels is to avoid all exertional activity, but this robs the patient of the many health benefits of exercise. The best available exercise recommendations in vEDS are derived from those for other connective tissue related vascular diseases, such as Marfan syndrome and Loeys Dietz Syndrome. However, these syndromes are defined by a reliable pattern of aneurysm formation, followed by dissection and rupture and do not mimic the unpredictable vascular ruptures seen in vEDS. Currently, vEDS patients are advised to avoid “burst” exertions and contact sports, which generally translates to avoiding all competitive sports and significant weightlifting. However, the exercise guidelines in this disease are severely lacking in evidence-based recommendations.
In our lab, we have a mouse model of severe vEDS which we have utilized to begin to investigate questions with respect to two major categories of exercise: dynamic or “cardiovascular” (running, swimming, biking, etc) and static or “isometric” (pull-ups, pushups, planks, resistance training). To assess the effects of cardiovascular exercise, we used treadmill running. To assess the effects of isometric exercise, we utilized inverted suspension with mice supporting their own weight against gravity for an extended interval. In our preliminary studies, we noted that consistent moderate cardiovascular exercise did not result in an increased rate of vascular rupture in these mice. We also discovered that isometric exercise actually increased overall survival, particularly in female mice. None of the female vEDS mice on an isometric exercise regimen died, which is significantly different than the 50% mortality rate observed in non-exercised vEDS controls. This points to isometric exercise as a potential beneficial adjunct in the treatment plan of vEDS patients. Financial support from an EDS Society microgrant would allow us to further investigate these preliminary findings and determine a mechanism for these observed differences that will inform further research in and future recommendations on exercise for patients living with vEDS.

Primary Investigator:
Dr. Rebecca Sorber
Johns Hopkins University School of Medicine
733 N Broadway,
Baltimore, MD 21205,
United States


Proteome profiling for hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders to unravel pathogenetic mechanisms and identify potential biomarkers supporting clinical diagnosis.

Hypermobile Ehlers-Danlos syndrome/Hypermobility spectrum disorders (hEDS/HSD) is characterized by generalized joint hypermobility, musculoskeletal pain and minor systemic manifestations without a known molecular basis. Hence, its recognition remains an exclusion diagnosis based on a new set of clinical criteria. From a point of scientific view, a detailed knowledge of the pathogenetic mechanisms is an essential starting point for the development of targeted management/therapies for highly disabling signs that considerably reduce the quality of life and working ability of hEDS/HSD patients. Therefore, unraveling the complexities underlying the etiology of hEDS/HSD and their pathogenetic link with musculoskeletal pain will surely help in having a more feasible diagnostic assessment and/or prognostication of the disorder, and improving the knowledge in mechanisms of musculoskeletal pain generation and chronicization. Musculoskeletal pain is a great burden for the general population in most developed Countries. The proposed research may have a translational relevance and impact for the National Health Systems, considering the huge number of hEDS/HSD patients (several hundred patients with hEDS/HSD clinically evaluated in our Center) and thus reaching a definite diagnosis will stop the expensive and lengthy diagnostic process for these individuals. Furthermore, the disclosure of the pathogenetic background of these patients will lead to the development of targeted management/therapies that will decrease the prescription of ineffective drugs and unnecessary evaluation, ameliorating patients’ management and treatment of the disease, likely contributing to the improvement of their healthcare. In this scenario, the findings that will derive from the present research activity could address towards future research for the identification of serum diagnostic biomarkers, which might be a promising approach for non-invasive diagnostic test for hEDS/HSD patients.

Primary Investigator:
Marina Colombi, PhD
Full Professor of Medical Genetics
Department of Molecular and Translational Medicine Institution
University of Brescia
Viale Europa, 11 – 25123
Brescia, Italy

Outcomes of aortic and arterial surgical interventions in individuals with vascular Ehlers-Danlos syndrome

We know that lifespan for individuals with vEDS is shortened compared to unaffected family members but we are uncertain if the timing and nature of surgical and medical intervention for some of the catastrophic complication improve outcome and, if not, what would be a better form of treatment or surveillance. Our own records of some 1250 individuals with vEDS often provide only rudimentary details of the complications. We plan to obtain the medical records from this group and others through the ED Society registry and the vEDS Collaborative study from about 1000 individual with vEDS documented by genetic testing. We want to discover if medical intervention can be substituted for surgery, or endovascular vascular treatment can be substituted for open surgical treatment, and we want to know if there are details of surgery and post-operative care that can be changed to facilitate long-term survival. To do this study we will obtain the detailed medical records from about 1000 individuals with COL3A1 mutations and review their history and interventions. We will then determine if medical treatment can suffice in some situations and whether stenting is better than open surgery. We will also determine if fluid overload, a common event after surgery, is a great hazard in this group.

Primary Investigators:
Sherene Shalhub, MD, PhD, and Peter Byers, MD
University of Washington
1959 NE Pacific Street
Box 35641
Seattle, WA 98195

Exploring Causal Pathways for Chronic Musculoskeletal Pain in the Ehlers-Danlos syndromes

Chronic pain is a major complaint in EDS patients. It is, to variable extent, observed in all EDS subtypes, and a frequent reason for seeking medical help. It has a severe impact on daily activities, quality of life and psychosocial functioning. Severe chronic pain can even shorten life expectancy. Nonetheless, currently used pain therapies do not result in adequate pain relief, and are associated with serious health risks. Chronic EDS-pain thus represents an unmet medical.

Despite it being a huge clinical problem, it is at present unclear how pain starts and evolves over time in the different EDS subtypes. Most EDS subtypes are caused by defects in the biosynthesis of connective tissue, the tissue that supports and protects the body. Connective tissue is found in between other tissues everywhere in the body, including the nervous system. We hypothesize that aberrations of the connective tissues, caused by the genetic defects underlying EDS, lead to structural and/or functional changes in the peripheral and central nervous system, and that these changes generate and maintain
EDS-associated pain.

In order to explore this hypothesis, we will:
(1) assess and characterize pain and explore pain mechanisms in a cohort of cEDS and hEDS
patients, using validated questionnaires and experimental pain testing.
(2) assess pain-related behaviors in a validated mouse model for cEDS. Animal models provide the advantage of allowing in-depth studies of affected tissues, e.g. nervous tissue. We will document whether pain is accompanied by anatomical, molecular and cellular changes over time in the peripheral and central nervous tissues using state-of-the-art imaging and sequencing techniques.

We anticipate that our study will provide unprecedented insights into EDS-associated pain and associated changes in the nervous system. Our ultimate goal is to identify potential therapeutic targets for the development of better pain therapies for all EDS subtypes.

Primary Investigator:
Fransiska Malfait MD, PhD
Senior Clinical Investigator, Head of Clinic Department
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent

Refining and improving the Ehlers Danlos Syndrome Variant Database

Ehlers Danlos Syndrome (EDS) is a heterogeneous group of inherited disorders characterised by well recognised signs and symptoms in various organs and tissues of the body. The mutations that cause EDS, especially vascular EDS, are many and varied in their nature. They also occur in several genes that encode both enzymes and structural proteins. The best way to make sense of these disease-causing mutations is to collect them systematically and put linked accounts of the mutations and patient symptoms into a database. This allows researchers and clinicians to spot trends and to improve decision making in health care.

The Ehlers Danlos Syndrome Variant Database ( provides comprehensive access to sequence variant data relating to the genetic basis of the various types of Ehlers Danlos syndrome (EDS). There is excellent evidence that the database is widely used by both researchers and clinicians.

Mutation data have been collected for more than thirty years and are currently hosted in a purpose-built database that allows easy and free access to the data. Until about two years ago the maintenance of the data in the database, including the addition of new data, was a manageable task that could be accomplished without help or financial support. However, the rate of accumulation of new mutation data, brought about by the development of new diagnostic tests, has resulted in the need for financial support to ensure that the database can be maintained to the same high standard that was previously achievable.

The database software that is currently used is outdated and unsupported and proper funding of this endevaour would allow the database software and the disease-causing variant data content to be brought up to date.

A comprehensive programme of updates and improvements to the database is proposed, including a change to where the database will be hosted. These measures will ensure an improved user experience and also safeguard the long-term viability of the database. This would bring about much-needed improvements to what the database offers the EDS community: researchers, medical staff, and the patients themselves.

Primary Investigator:
Raymond Dalgleish PhD
Professor of Human Genetics
Department of Genetics & Genome Biology Institution
University of Leicester
Leicester, LE1 7RH

Examining global gene expression in skin biopsies from people with hypermobile EDS

Hypermobility Ehlers Danlos Syndrome (hEDS) is the most common of the 13 EDS subtypes. It is also the only subtype without identified causative genes. This study supports analysis of gene expression (RNAseq) in people with hEDS compared with normal controls. The goal is to identify genes that are differentially expressed in hEDS, thus pointing to relevant pathogenic processes and supporting candidate genes found in whole genome sequencing.

Primary Investigator:
Christina M. Laukaitis, MD, PhD, FACP, FACMG
Director, Genetic Consultation and Counseling Services, UAHS Center for Applied Genetics and Genomic Medicine


HEDGE — Hypermobile Ehlers-Danlos Genetic Evaluation

This research endeavor represents the most comprehensive, collaborative effort to date in seeking to understand the underlying causes of hypermobile Ehlers-Danlos syndrome at the level of genes and gene expression. If we can achieve a better understanding of the underlying genetics and the gene expression abnormalities, we may be able to develop diagnostic tests and find more specific treatments for hypermobile EDS—and, potentially, the hypermobility spectrum disorders.

There have been great strides in biotechnology over the last two decades and the ability to understand and find treatments for genetic syndromes is at a turning point. Detailed research into the underlying issues causing hEDS and HSD will help determine where to target therapy. This genome sequencing study is the next step in our overall project to make the hope of these new technologies a reality.

Primary Investigator:
Hypermobile Genetic Research Network

Body Awareness Therapy as Treatment for Chronic Pain

People with Hypermobility Spectrum Disorder (HSD) often have pain, coordination problems, and low tolerance to activity and exercise. Body awareness training, such as Feldenkrais, may help people manage these challenges. This pilot study will have a convenience sample of 10 individuals with symptomatic Hypermobility Spectrum Disorder (HSD) participate in a 12 session Feldenkrais program to teach body and movement awareness. Feldenkrais is a form of movement retraining aimed at improving efficiency and reducing muscle guarding and pain during movement.  It uses guided visualization techniques during small movements to help the individual explore using stabilizing muscles in a safe range of motion.  It is a type of mindful movement that has been used successfully for managing chronic pain. The goal of this pilot study is to see whether participants in the Feldenkrais program report decreased pain, improved function, and improved self-efficacy (confidence in their ability to take care of themselves). If there are improvements in any of these outcomes, we hope to be able to determine whether these changes are related to improved self-awareness (interoception) or decreased fear of movement (kinesiophobia). Another potential benefit from this research will be to establish a research design framework for clinicians interested in performing similar pilot studies using other body awareness therapy approaches such as Pilates, Tai Chi, etc.. Clinician-led pilot studies such as these can lead to future, more definitive randomized control studies.

Primary Investigator:
Leslie Russek, PT, DPT, PhD, OCS
Physical Therapy Department
Clarkson University
Potsdam, NY, 13699-5880

Accessing Chronic Pain in Pediatric Patients with EDS/HSD

Multidisciplinary pain management is recommended as best practice to not only reduce pain, but also to improve functional ability, when providing care to children and adolescents with chronic pain. As children with hypermobile Ehlers Danlos Syndrome (hEDS)/hypermobility spectrum disorder (HSD) have an increased risk of injury and prolonged recovery time post injury, standard multidisciplinary pain programmes may not be as effective for children with hEDS/HSD. However, we currently don’t know if the chronic pain experience and associated symptoms of children with hEDS/HSD is similiar to that of their non-hEDS/HSD peers. We also don’t know if the outcomes from multidisciplinary pain management is different for children with hEDS/HSD than that of their unaffected peers. A better understanding of these differences may assist us to develop tailored multidisciplinary chronic pain management programmes for children with hEDS/HSD.

Children attending the main paediatric chronic pain clinics in Sydney, Australia, have been recruited into this study which is currently underway. We are measuring how many children attending have generalised HSD (G-HSD) or hEDS. Each child completes questionnaires about their pain, fatigue, mental health, and other symptoms at initial presentation and again 6 months later, including their global impression of change and satisfaction with multidisciplinary pain management services. , however children with G-HSD reported significantly lower functional abilities than their non-hypermobile peers.  Results of this study will provide critical data to assess the potential need for future studies assessing the efficacy of a hypermobility-specific intervention designed to reduce pain of children and adolescents with G-HSD/hEDS, and allow for immediate translation of findings into current clinical practice.

Primary Investigator:    
Verity Pacey B App Sci (Phty), PhD
Senior Lecturer
Department of Health Professions | Faculty of Medicine and Health Sciences
G815, 75 Talavera Rd
Macquarie University, NSW 2109, Australia​

Dentition, Orofacial Function And Craniofacial Characteristics Of Patients With Ehlers Danlos​ ​syndrome

The Ehlers-Danlos syndrome (EDS) is a hereditary disorder affecting the connective tissue and collagen​ ​structures in the body and is characterized by joint hypermobility, skin hyperextensibility and tissue​ ​fragility.

Several types of EDS have been identified and may affect structures in the mouth including early onset​ ​inflammation of the tissues around the teeth, abnormally shaped roots and functional problems in muscles​ ​and the temporomandibular joint, which impede diagnosis and treatment. Sleep-disordered breathing (SBD) has recently been reported in EDS and is often associated with specific characteristics of the​ ​craniofacial profile. The aim of this Danish study is to examine the teeth, the chewing function, th​e ​craniofacial profile and upper respiratory tract of patients with EDS compared to a healthy age and gender matched control group. The hypothesis of the study is that there will be differences in teeth, function,​ ​craniofacial profile and upper respiratory tract between patients with EDS and a healthy control group. The​ ​results will contribute to a better understanding of the characteristics of EDS and thus improve diagnostics and treatment of EDS. In addition, this new knowledge is relevant for dentists as many dentists meet​ ​patients with EDS in their daily clinic.

Primary Investigator:
Liselotte Sonnesen
Leder af specialtandlægeuddannelsen i Ortodonti
Specialtandlæge i Ortodonti, ph.d., dr.odont
Det Sundhedsvidenskabelige Fakultet

Fagområde Ortodonti
Københavns Universitet
Nørre Allé 20
2200 København NDIR 35326670

Understanding Increased Pain in TNX deficient and hEDS patients

In the past 15 years, scientific advances has led to acceptance amongst medical professionals that​ ​bowel symptoms are very common in hypermobility related disorders, in particular, the hypermobile​ ​Ehlers​-​Danlos (hEDS) subgroup. This group of patients have a problem with the extracellular matrix​ ​(ECM) which is the scaffold that keeps joints and organs intact. Patients with hEDS experience symptoms similar to those who have Irritable Bowel Syndrome thereby​ ​constituting a strong link​ ​between the two types of conditions. If we can find the basis for this link, we can design or optimise​ ​medications to manage the bowel symptoms that address the main abnormality in the tissues that causes these disorders. Thus it will be easier to intervene with patients susceptible to abdominal (tummy) pain​ ​constipation and/or rectal prolapse using existing or novel treatments. Finally, it will make a major​ ​difference for patients to know what is the root of their problem, which is not currently the case in the​ ​majority of patients with functional gut disorders (where cause is not known).

Previously we have characterised a type of ECM tissue called Tenascin X (TNX) in the mouse and​ ​human gut and found that it is important for gut function. We now want to understand why abdominal pain​ ​is common in patients with hEDS and in TNX deficiency. If a clearer picture of why pain is common in​ ​patients with connective tissue disorders is found, it would pave the way for better diagnosis and​ ​treatment. We have obtained a TNX knockout mouse (where the TNX gene has been removed), and​ ​developed purpose-designed techniques and have investigated TNX role in several gut functions. In​ ​particular we have studied how TNX influences the function of nerves that control sensation and​ ​movement of the gut. For this grant we would like to use TNX-KO mouse model to explore the reason​ ​for increased pain in TNX deficient and hEDS patients. We have obtained stomach and gut biopsies​ ​from patients diagnosed with hEDS, which we will study to see how different pain nerves look​ ​compared to biopsies from normal people.

Primary Investigator:
Dr Rubina Aktar
Queen Mary University of London​