The Ehlers-Danlos Society aspires to offer grants annually, with calls for clinical research proposals early in the year and for basic science later in the year. We will also offer grants of varying value to reflect the different nature of researcher requirements, including microgrants.
As a researcher, please look out for announcements of grant-funding rounds on our website, here.
$330k Grant
Research and Educational Support in EDS
The funds from this gift/grant will be used to explore new gene candidates for hEDS. By taking the genetic variants that we identified in hEDS patients, we can validate whether these potential mutations (or variants of unknown significance) are relevant to causing hEDS. Through these studies, new models will be generated that will allow us to test how genotype can correlate with phenotype and various co-morbidities found in the patients.
$150,000
Primary Investigator:
Russell Norris
Medical University of South Carolina
Charleston, South Carolina, USA
Research and Educational Support in EDS
Our lab uses mouse models of vascular Ehlers-Danlos syndrome (VEDS) to try to understand the underlying mechanism that drives vascular fragility and rupture. In this manner, we hope to develop new treatment strategies for VEDS. While substantial progress has been made in defining a list of abnormalities that occur in the walls of arteries in models of VEDS, we lack the ability to assign these abnormalities to specific cell types, or an understanding of how cells send abnormal signals to each other. We have now launched a comprehensive program to address these issues using state-of-the-art genetic technologies that allow identification of all the genes that are turned on or turned off in thousands of individual cells in the aorta, and to look at how these gene signatures vary based upon the specific location of a given cell, including consideration of what cell types are immediately next door. This profiling will be performed in VEDS mice that are either vulnerable to having a vascular event or protected based upon manipulation (such as use of a medication). In this manner we hope to identify new drug targets, predict at-risk vascular segments for more frequent imaging or surgical intervention, and identify a protein in the bloodstream (a so-called biomarker) that can help to monitor disease progression or an individual’s response to treatment. We are very excited about this research direction and thankful to the EDS Society for the opportunity to perform this work.
$150,000
Primary investigator:
Hal Dietz
John Hopkins University
Baltimore, MD, USA
Research and Educational Support in EDS
$30,000
Primary investigator:
Rebecca Bascom
The Pennsylvania State University
Pennsylvania, PA, USA
Rarer Types of EDS
Unraveling The Mechanisms Underlying Vascular Fragility In Classical-like Ehlers-Danlos Syndrome: An Integrated Approach
$80,000
Primary investigator:
Ulrich Valcourt
University Lyon
Lyon, France
Dissecting The Significance and the Impact of Missense PLOD1 Mutations Causing Kyphoscholiotic Ehlers-Danlos Syndrome
$120,000
Primary investigator:
Frederico Forneris
University of Pavia
Pavia, Italy
Microgrants Round One
Investigating the mechanical properties of a tissue-like three-dimensional cell model mimicking EDS skin hyperextensibility
$5,000
Primary Investigator:
Catherine Bui
Université de Lorraine
France, Nancy
Sex and Age Differences in Comorbidities in hEDS vs. HSD
$5,000
Primary Investigator:
Dacre Knight
Mayo Clinic
Florida, United States
Generation Of Zebrafish Models Of Classical Ehlers-Danlos syndrome
$5,000
Primary Investigator:
Delfien Syx
Ghent University
Ghent, Belgium
Elucidating the genetic basis of Ehlers-Danlos syndromes using whole genome sequencing
$5,000
Primary Investigator:
Fransiska Malfait
Ghent University
Ghent, Belgium
Cost of illness for Ehlers-Danlos syndromes in the United States: Patient and Family Perspectives
$5,000
Primary Investigator:
Jane Schubart
Penn State College of Medicine
Pennsylvania, United States
Chronic pain and fatigue during walking in hypermobile EDS: are the muscles to blame, and what can we do about it?
$5,000
Primary Investigator:
Jared R Fletcher
Mount Royal University
Calgary, Canada
Determining Sex Hormone Effects on Symptom Exacerbation And Abatement Across The Complete Menstrual Cycle
$5,000
Primary Investigator:
Jennifer Andrews
University of Arizona
Arizona, United States
Data Optimized Patient Journeys for Individuals with Ehlers-Danlos: Artificial Intelligence-Supported Clinical Profiling
$5,000
Primary Investigator:
M.C Scheper
Hogeschool Rotterdam
Rotterdam, Netherlands
Prevalence and severity of psychological symptoms and factors in hypermobile Ehlers-Danlos Syndrome and hypermobility spectrum disorders
$5,000
Primary Investigator:
Ranita Manocha
University of Calgary
Calgary, Canada
Integrative medicine for hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS): A mixed-methods feasibility study
$5,000
Primary Investigator:
Sara Guedry
National University of Natural Medicine
Portland, Oregon
Microgrants Round Two
Analysis of Pain, Psychosocial Factors, and Joint Biomechanics in Children with Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder
$5,000
Primary Investigator:
Hyo Jung Jeong
University of Wisconsin
Milwaukee, USA
Validation of a Novel Patient-Reported EDS Disability Index
$5,000
Primary Investigator:
Emily Rosario
Casa Colina Hospital and Centers for Healthcare
Pomona, USA
The Ehlers-Danlos Syndromes: A consensus of treatment options for the management of cutaneous disease
$5,000
Primary Investigator:
Brent Doolan
Cambridge University Hospitals
Cambridge, UK
Investigating bone fragility in a mouse model of Brittle Cornea Syndrome caused by mutation in Zfp469
$5,000
Primary Investigator:
Veronique Vitart
University of Edinburgh
Edinburgh, United Kingdom
Understanding biomechanics of atraumatic shoulder pain and instability in EDS and HSD
$5,000
Primary Investigator:
Marta Jokiel
Poznan University of Medical Sciences
Poznan, Poland
Assessing Oculomotor Function and Fall Risk in the EDS Population
$5,000
Primary Investigator:
Laurie Jahnke
Boro Medical Clinic
Murfreesboro, United States
Surviving their Stripes: Quality of Life and Coping for Individuals with Ehlers-Danlos syndrome
$5,000
Primary Investigator:
Julie Hill
Auburn University
Auburn, United States
Patient Understanding of Disease and Clinical Needs After Diagnosis of Ehlers-Danlos syndrome
$5,000
Primary Investigator:
Jordan Jones
Children’s Mercy Kansas City
Kansas City, United States
Research Support
Research and Educational Support in EDS
$70,000
Primary Investigator:
Russell Norris
Medical University of South Carolina
Charleston, South Carolina, USA
Molecular Studies in hEDS and HSD $1 Million Grant
Unraveling the path mechanisms underlying hypermobile Ehlers-Danlos syndrome: an integrated omics approach
Insights into the mechanisms that cause disease in hypermobile EDS (hEDS) remain scarce. An important reason for this is the huge variation in clinical presentation among hEDS patients, which makes it unlikely that a single genetic defect will be responsible to cause this condition, but at the same time, it also makes it hard to pinpoint the exact molecular cause. Nevertheless, given the overlap of clinical symptoms with other EDS subtypes, that lead to abnormalities in the extracellular matrix (ECM), especially with classical EDS (cEDS), it is likely that the mechanisms underlying hEDS also affect the ECM to a certain extent.
Today, several technological advances make it possible to obtain and investigate large, complete datasets of all the DNA (genome), the RNA (transcriptome), and the proteins (proteome) in a particular tissue or cell type from an individual. It is known that in disease states, changes can be observed at these three levels. However, the extent of these changes in hEDS is currently not known.
In this study, we will perform these analyses on the skin and skin cells (fibroblasts) from two affected and one non-affected individual from 10 different hEDS families. In addition, we will also include skin and fibroblasts of 15 cEDS patients as a positive control since the genetic defect in these patients is known, and we will also include 10-15 healthy volunteers to compare the findings in hEDS and cEDS patients. Our approach is unique in the fact that we will investigate all datasets (genome, transcriptome, and proteome) for each of the selected individuals. To the best of our knowledge, this is the first time an integrative approach of this kind is applied to investigate this challenging condition.
The findings resulting from this research will be helpful to understand the defective mechanisms in hEDS, but also in cEDS. Moreover, this approach may result in the identification of (a) prognostic biomarker(s) for disease progression and the development of complications, such as chronic widespread pain or other symptoms. The knowledge obtained from these studies may also be useful for hypermobility spectrum disorder (HSD) patients and patients with other EDS subtypes. These findings may ultimately have an impact on the classification and/or grouping of these patients, eventually resulting in faster diagnosis, more effective management, and better counseling.
$200,000
Primary Investigator:
Delfien Syx
Ghent University
Ghent, Belgium
Using the power of multi-omics and precision medicine to unravel the biology of hEDS and HSD
Complex Chronic diseases account for nearly two-thirds of deaths worldwide and most health-care expenditure in the USA, thereby representing a major challenge to global health in the 21stcentury. With advances in technology, many promising tools have been created to better utilize precision medicine to improve diagnosis, treatment, and preventive strategies regarding complex comorbid conditions. However, there is a large gap between routine medical practice and the implementation of all these new tools and pipelines, creating a huge hurdle in treating patients with complex chronic conditions. Ehlers-Danlos syndrome, a group of related hereditary disorders that affect connective tissues are prototypical examples of complex chronic diseases, affecting millions of people worldwide.
EDS hallmark features involve joint hypermobility, soft and hyperextensible skin, abnormal wound healing, and easy bruising. However, the genetic and epigenetic variation can affect the degree of skin hyperextensibility and joint hypermobility and also some additional clinical features that differ among EDS subtypes, such as the fragility of soft tissues, vessels, and hollow organs, early-onset periodontal disease, and involvement of the musculoskeletal system. Variation in clinical presentation and symptoms’ severity and the reduction in the degree of hypermobility due to factors such as aging, arthritis, and surgeries can cause ambiguities in clinical recognition between different classes of EDS. So far 14 classes of EDS have been identified, for those mutations in a handful of genes have been reported to be causal. However, the genetic causes of hypermobile EDS (hEDS), the most common type of EDS, and hypermobility spectrum disorders (HSD) are still unknown.
hEDS/HSD tends to run in families, suggesting a role for genetic predisposition in the development of the disease. Families with hEDS/HSD history also have a high burden of other comorbidities such as chronic fatigue syndrome, post-treatment Lyme disease syndrome, pediatric acute-onset neuropsychiatric syndrome, postural orthostatic tachycardia syndrome, GI disorders, small fiber neuropathy, craniocervical instability, sleep disorders, and anxiety. These indicate that family-based multi-omics studies are extremely valuable in understanding the genetic susceptibilities and molecular basis of hEDS/HSD, as the background genetic variation and environmental exposures are controlled to some extent. Here, we propose to conduct a comprehensive longitudinal multi-omics study on blood samples collected from multiple families with hEDS/HSD. This research will provide a deeper understanding of the underlying genetic and epigenetic risk factors associated with hEDS/HSD. Integrating the multi-omics data with participants’ clinical information will provide a causal mechanistic model of hEDS/HSD and help us to investigate key factors that can be therapeutically targeted or used as biomarkers, as well as insights into pathogenesis and heterogeneity. The long-term goal of this study is to develop novel blood-based biomarkers for more feasible and cost-effective diagnostic and/or prognostic assessment of hEDS/HSD and also identify therapeutic targets and strategies improving patients’ care; we have therefore assembled a team ideally suited to take on this challenge.
$200,000
Primary Investigator:
Fereshteh Jahaniani
Stanford University
Palo Alto, USA
Molecular, biochemical, and genetic mechanisms underlying connective tissue dysfunction in hEDS
The Ehlers Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and genetic variation among the various thirteen subtypes. The initial genetic findings on EDS were related to changes in collagen but the causes of the many subtypes revealed several genes not involved in collagen production. However, the genetic basis of the hypermobile type of EDS (hEDS) is not known.
hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several co-morbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on a combination of age, gender, lifestyle, and the likely multitude of genes involved in hEDS.
Our studies initiated with a large family that presented with inherited hEDS. Through our genetic studies, we were able to identify a mutation in a putative causal gene. This mutation was found in each of the nine affected individuals throughout four generations of the family and none of the non-affected individuals. Since this initial discovery, we have successfully generated a mouse model with the corresponding human mutation. These mice have phenotypes consistent with hEDS, therefore validating the mutation as causative. In this proposal, we wish to add to these studies by uncovering not only how the mutation causes disease, but also identify additional causative mutations in large families with hEDS. These studies will identify why patients have defects in connective tissues and will indicate how we can develop treatments to help those with hEDS.
$200,000
Primary Investigator:
Russell Norris
Medical University of South Carolina
Charleston, USA
Hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: destructuring the fibroblast secretome to define bioactive molecules and disease mechanisms, and in vivo translational studies
Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, musculoskeletal pain, and other systemic manifestations without a known molecular basis. Therefore, its recognition remains an exclusion diagnosis based on a new set of strict clinical criteria. Patients with symptomatic joint hypermobility who did not fulfill these new diagnostic criteria are currently classified as hypermobility spectrum disorders (HSD).
The present proposal aims to unravel, by integrated molecular, biochemical/physical, and nanoscience approaches, bioactive key molecules, and pathophysiological mechanisms associated with these conditions. We previously demonstrated that hEDS and HSD cells shared a pro-inflammatory matrix-degrading phenotype with a range of cellular features that are typical of myofibroblasts. Cellular proteome profiling of hEDS myofibroblasts revealed changes in the expression of a subset of proteins mainly implicated in cellular metabolism, redox balance, extracellular matrix (ECM) homeostasis, cytoskeleton organization, protein folding into the endoplasmic reticulum, intracellular trafficking, and secretory pathway. Proteome analysis of hEDS cells-derived culture media (CM) discovered altered levels of several ECM structural components (including collagens, fibronectin, and proteoglycans), matrix metalloproteinases and their inhibitors, and further secreted proteins predicted to be located in extracellular vesicles (EVs), which likely contribute to the excessive ECM degradation and concomitant acquisition of the peculiar myofibroblast-like phenotype. Furthermore, preliminary data obtained treating control fibroblasts with patient cells’ CM-derived soluble factors and EVs suggested that both these fractions may act synergistically to induce the disease phenotype.
In the present project, we plan to corroborate and deepen our previous proteome and secretome findings through targeted in vitro functional studies on interesting, emerged biomolecules both in hEDS and HSD myofibroblasts, to decipher mechanisms of action and functional significance within specific disease pathways to support their diagnostic application and possible future use as therapeutic targets. We also project to dissect the secretome composition of hEDS and HSD myofibroblasts, by fractioning it into soluble macromolecular components (MCs) and different sized-EVs, to uncover specific RNA species (including miRNAs), secreted bioactive mediators, and associated disease pathways that may contribute to the hEDS and HSD pathomechanisms.
This research, followed by targeted in vivo translational studies on patients’ serum/plasma, should contribute to the elucidation of the etiopathogenesis of hEDS and HSD, offer the possibility to identify potential biomarkers defining whether these disorders are part of a phenotypic spectrum rather than distinct clinical entities and, ultimately, pave the way to the development of targeted therapeutic strategies with a potential benefit for patients’ management. Considering the huge number of hEDS and HSD patients, the project could have a large social and economic impact. Indeed, reaching a definite and certain diagnosis will stop the expensive and lengthy diagnostic process and the development of targeted therapies will decrease the prescription of ineffective drugs and unnecessary evaluations, improve patients’ quality of life, and alleviate their disabilities.
$200,000
Primary Investigator:
Marina Colombi
University of Brescia
Brescia, Italy
Hidden Genome in hEDS Resolved by Third-Generation Sequencing
Many people consider Ehlers-Danlos syndrome to be one condition. However, our current understanding is more of a family of disorders, each with its own genetic cause and unique features. Recent advances in genetic technology have allowed for the discovery of the causes for several rare types of EDS. Hypermobility types EDS (hEDS) is the most common form of EDS, and although updates to the diagnostic criteria in 2017 improved our ability to appropriately diagnosis hEDS, they are not perfect. It would be extraordinarily helpful for patients if we were able to understand more about the underlying cause(s).
Earlier research trying to answer this question suggested that a gene known as TNXB may be responsible for both some cases of hEDS and a different type of EDS known as classic-like EDS (clEDS). It is likely that this is true, but this has proven to be a difficult gene to understand, and at best it represents a very small percentage of hEDS patients. Therefore, much remains to be learned about the causes of hEDS. Previous research has used a method known as whole-exome sequencing (WES) which analyzes only the parts of the human genome that code for protein products and has thus far not been successful in findings causes of hEDS. Current efforts to use whole-genome sequencing (WGS) to investigate the cause of hEDS offer additional potential for gene discovery, but the technology itself has limitations.
We propose asking the question of the cause of hEDS in diverse ways.
First, given the nature of our clinic, we can recruit significant numbers of entire families of affected patients and compare them to other unaffected relatives. This will increase the likelihood that helpful results will be obtained.
Second, we will use the existing infrastructure of the Genomic Answers for Kids program to evaluate for known genetic disorders which may look like hEDS but have different genetic causes. We have already found several such patients in this study but anticipate that there are more.
Third, genomic research thus far has generally used next-generation sequencing (NGS) technology for “short read” WES and WGS. NGS produces many small pieces of DNA that are then aligned by computer so that the entire sequence can be analyzed. Because the individual pieces of DNA are so small, there are many areas of the human genome that NGS cannot accurately analyze.
This study proposes using 3rd generation long-read WGS for patients with a clinical diagnosis of hEDS and no diagnosis found on standard short read WES. Having a longer length to each sequenced DNA strand is beneficial for analyzing areas that NGS is unable to accurately analyze. This includes certain types of spelling errors and larger changes to the structure of the DNA. Fourth, we will use a person’s individual sequence to compare to “normal” references to look for extra pieces of DNA. In conclusion, we feel that the expertise and novel approach that Children’s Mercy Kansas City brings to this project offers significant potential for discovering the causes of hEDS.
$ 200,000
Primary Investigator:
Tomi Pastinen
Children’s Mercy Hospital
Kansas City, Missouri
Basic Science Research Major $400k Grant
Sexual Dimorphism in Vascular Ehlers-Danlos Syndrome: Mechanistic and Therapeutic Implications
Vascular Ehlers-Danlos syndrome (vEDS) is caused by heterozygous mutations in the gene (COL3A1) encoding type III collagen. Patients are highly predisposed to spontaneous tear or rupture of arteries throughout the body, the intestines or the pregnant uterus, often leading to premature death. Puberty is a time of heightened risk for a catastrophic vascular event in vEDS, particularly in males. We developed a mouse model of vEDS by introducing a DNA change that was previously observed in patients with vEDS into the corresponding mouse gene. Our goal is to use this model to better understand how deficiency of type III collagen leads to the clinical problems seen in vEDS and to identify and test new treatment strategies. Using our mouse model, we observe a great acceleration of aortic rupture as they go through puberty, mirroring observations in young men with vEDS. As expected, this was particularly evident in male vEDS mice, but also seen to an extent in females. It is our firm belief that unraveling the mechanism of sex differences in vEDS will inform the fundamental basis of the disease process, with the strong potential of adding to therapeutic options for all vEDS patients.
One candidate event that attends puberty in males is the release of high levels of male sex hormones (called androgens) such as testosterone. Androgens also rise in females at puberty, but to a lesser extent than males. We tested the hypothesis that androgens are contributing to puberty-associated vascular rupture by treating male and female vEDS mice with a potent inhibitor of the androgen receptor called bicalutamide in combination with hydralazine, a drug that prevents vascular events prior to puberty; dramatic protection was observed in both sexes. Given the potential for side effects related to use of a potent androgen blocker, we tested a drug called spironolactone that also inhibits androgens, albeit more gently, and is used to treat a variety of disorders in people of both sexes. The combination of hydralazine plus spironolactone prevented vascular events in male and female vEDS mice through puberty and beyond.
We are just beginning to learn about how androgens contribute to the risk of vascular disease in vEDS. Our ongoing and future studies will comprehensively address this critical issue using the most advanced molecular methods to define the detrimental response of vascular cells to a deficiency of type III collagen, to elucidate how androgens amplify these abnormalities, and to characterize molecular changes that attend successful treatment of vEDS with androgen blocking agents. We will also determine the precise cell type or types that are responsive to androgens in the vessel wall. This will be accomplished by selectively removing the androgen receptor gene in specific cell types in vEDS mice using powerful genetic strategies. Our expectation is that we will observe overt protection when the androgen receptor is deleted in one or more critical cell types. This will allow future efforts to develop new treatments for vEDS to focus on events and cells that specifically contribute to disease.
$150,000
Primary Investigator:
Dr. Harry Dietz
John Hopkins University
Baltimore, Maryland
Investigating intrinsic platelet dysfunction in Ehlers-Danlos Syndrome
Major bleeding caused by tearing of large blood vessels is a serious complication in Ehlers-Danlos syndrome (EDS). However, many patients also suffer from mild-to-moderate bleeding such as easy bruising, abnormal uterine bleeding, or excessive bleeding after surgical procedures. The ability of the body to stop bleeding, called hemostasis, depends on the normal function of blood cells called platelets. These are small cells that flow through blood vessels along with red blood cells, and whenever there is damage to a blood vessel, platelets stick to the damaged area to plug the hole and stop bleeding.
Several subtypes of EDS are caused by changes in the molecules that make up blood vessels, which is what can cause them to break easily. However, these molecules are also important for allowing platelets to stick to the injured vessel, so this causes platelets to function less effectively in some EDS patients. However, there are studies that suggest that even when you test patient platelets in a test tube, they still show signs of dysfunction. If the platelets themselves are dysfunctional, on top of the changes to the blood vessel molecules, this could worsen bleeding in some EDS patients. The objective of this proposal is to determine whether platelets are dysfunctional in EDS using both a mouse model and patient samples and determine how this impacts the effectiveness of certain therapies to prevent or treat bleeding. The big picture goal is to identify other bleeding risks in EDS patients to better predict and treat bleeding.
$63,000
Primary Investigator:
Robert Lee
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, USA
Investigating pain-related phenotypes in a mouse model of Ehlers-Danlos syndromes
Chronic pain is a main symptom in patients diagnosed with Ehlers-Danlos syndromes or hypermobility spectrum disorders and is an important reason to seek medical attention. It has a larger impact on 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 refractory to currently used treatments. An important reason for this is the lack of studies investigating the mechanisms and pathways that initiate and maintains pain associated with EDS.
Animal models can give valuable insight into mechanisms and pathways that are affected in human disorders. Several mouse models exist for different EDS subtypes. Our previous work demonstrated for the first time the presence of pain-related phenotypes in mouse models for classical; EDS due to defects in type V collagen and also showed accompanying changes in the interaction of the skin.
To better understand EDS-associated pain, more insights are needed including for example if the pathways leading to pain are similar or distinct in different EDS subtypes. Therefore, the general aim of this proposal is to document pain-related behavior in mouse models for dermatoparaxis EDS, caused by defects in ADAMTS-2, the enzyme that cleaves the N-propeptide of type 1 collagen. This model was chosen because patients with dermatoparaxis report progressive chronic widespread pain. To obtain this information, several behaviors and responses of these mice will be carefully monitored and analyzed. If pain-related behavior is observed, we will try to reverse the observed pain-related behavior by administering serval types of pain medication. In addition, the dermatoparaxis EDS mice will be crossed with specific reporter mice allowing them to visualize and study the nervous system in more detail. Finally, the obtained results for dermatoparaxis EDS mice will be compared with the available results for a classical EDS mouse.
$150,000
Primary Investigator:
Delfien Syx
Ghent University
Ghent, Belgium
Fall Microgrants 2020
Understanding Suicidal Behavior and Ideation in People with Hypermobile Ehlers-Danlos Syndrome
It is well known that chronic pain, physical disability, psychological distress, and female gender are risk factors for suicidal behaviors. These characteristics are overrepresented in people with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders (hEDS/HSD). Although research about suicidal behaviors in this population is very scarce, available data highlight an increased rate of suicide attempts among people with hEDS/HSD. Thus, the exploration of suicidality in those affected should not be overlooked. Unfortunately, no study has focused so far upon understanding more in-depth suicidality among individuals with hEDS/HSD.
Previously, we assessed suicidality in a group of patients with hEDS/HSD and characterized from a psychosocial point of view those presenting antecedents of suicidal attempts. This, with a quantitative approach. Following on from this study, we now want to explore qualitatively, how these patients understand and explain the causes of their suicidal behaviors and ideas, as well as their success or failure in overcoming the suicidal period. For that, a semi-structured interview will be proposed to patients with antecedents of suicide attempts and suicidal ideation in order to gain a more in-depth understanding of the participants’ experiences related to what led up to their attempts/ideas. The results of this qualitative research will fill a gap in the literature and will provide important insights to clinicians for caring for vulnerable patients and preventing the relapse of suicidal behaviors.
$5,000
Primary Investigator:
Dr. Carolina Baeza-Velasco
Laboratoire de Psychopathologie et Processus de Santé (EA4057)
Université de Paris
Physician Perceptions on Ehlers-Danlos and Other Heritable Collagen Disorders
One of the major concerns for patients with Ehlers-Danlos Syndrome (EDS) and related heritable collagen disorders is the lack of physician education and understanding surrounding these conditions. As such, patients often feel that their needs aren’t being met by the doctors they have entrusted with their care. Physicians treating patients with EDS feel a similar frustration, especially when trying to diagnose an adult. It is not known if this frustration for physicians stems from lack of knowledge surrounding heritable collagen disorders or paucity of treatment available to these patients. Physicians will be given surveys to determine their base knowledge surrounding EDS/ heritable collagen disorders as well as their Patient-Practitioner Orientation Scale (PPOS) score, which is a measurement of physician compassion. By assessing physician perceptions related to EDS, we hope to determine where physician education may be lacking. One on one interviews will be also conducted with physicians to determine how to best consolidate opinions and information into a CME accredited presentation, which will then be distributed to all physicians within the hospital network through the hospital-based e-learning platform.
$5,000
Primary Investigator:
Dr. Sara Strecker
Hartford Hospital
Care and Management of Children with Ehlers-Danlos syndrome: A Survey of Primary Care Providers
Ehlers-Danlos Syndrome (EDS) represents a family of heritable connective tissue disorders with overlapping phenotypic features that can be difficult to manage and treat. Current gaps in knowledge exist about primary care providers knowledge about care and management along with barriers to care and management of patients with EDS. Due to this lack of knowledge targeted educational information is limited. The long-term goal of this research is to gain an understanding of current knowledge and barriers to improve knowledge so that targeted educational strategies can be implemented to improve awareness and comfort with care and management of patients with EDS. The objectives of this application are to 1) characterize primary care provider understanding of care and management of patients with EDS, 2) identify barriers to improved awareness and ability to competently manage patients with EDS and 3) develop educational materials and program to improve understanding and knowledge of EDS. We suspect that most primary care providers are not comfortable with management of patients with EDS due to lack of understanding, which could be improved with increase in education. This study will assess primary care providers current knowledge and understanding about EDS, management experience of patients with EDS, clinical knowledge of EDS, and comfort providing primary care services to patients with EDS. It will also identify barriers noted by providers that prevent awareness and ability to manage patients EDS. With this information we will develop a novel educational program that improves knowledge and understanding of EDS that will address barriers and allow providers to better care for patients with EDS. We expect to provide strong evidence that to improve knowledge and understanding about EDS and to empower primary care providers to manage and care for patients with EDS we will need to understand the current knowledge and barriers that prevent better care of patients with EDS. Our research findings will be innovative as they will raise awareness to the need for better knowledge and understanding of EDS though recognized barriers and deficits in knowledge and understanding. This study will recruit 200 participants to complete an electronic survey dispensed via email sent to local and regional primary care providers. Participants will be asked questions that evaluate primary care providers current knowledge and understanding of EDS, their comfort with providing care to those patients and barriers to their understanding and management of patients with EDS. Completion of this proposed study will provide essential information to better understand the needs of primary care providers for the management of patients with EDS. Our future direction will include development of an educational program for providers to improve their understanding and confidence working with patients with EDS. The education program would be piloted with several groups of physicians to evaluate strengths and weaknesses. The goal would be to develop a seminar or webinar that would be available to medical providers. If successful in our region, it could be rolled out nationally.
$5,000
Primary Investigator:
Dr. Jordan Jones
Children’s Mercy Kansas City
Cannabis use in Ehlers-Danlos Syndrome and its effects on cognitive-motor processes
Cannabis is sometimes used therapeutically in those with chronic pain. Ehlers-Danlos Syndrome (EDS) is a group of genetic disorders where chronic pain is a common feature, but the effects of cannabis on cognitive-motor skills in EDS have never been studied and the rate of use in this population is largely unknown. In this study we seek to understand the immediate effects of cannabis on cognitive motor skills in those with EDS, in addition to exploring whether cannabis helps to control pain in this population. A small portion (11%) of EDS patients in a recent study from France, where both recreational and therapeutic use of cannabis is still illegal, reported using cannabis products to alleviate their chronic pain (Bénistan & Martinez, 2018). Recent changes in the legalization of cannabis in North America, has led to increased use of cannabis for both recreational and therapeutic purposes (Spindle et al., 2019). Indeed, in 2019, 18% of Canadians older than 15 reported using cannabis products within the last three months, which is notably higher than the 14% who reported the same just a year earlier, prior to its full legalization (Statistics Canada, 2019). Across a few of our previous studies, on proprioception in EDS, we noticed that a high number of patients mentioned using cannabis products therapeutically to lessen the widespread pain they experience daily. However, there have been no studies conducted to date which have reported the prevalence of cannabis use in North Americans with EDS. While cannabis use is often found to cause various cognitive-motor deficits, the degree of impairment is sometimes less evident among frequent users (Prashad & Filbey, 2013). Furthermore, other chronic pain populations have been found to show improvements in executive functioning following daily administration of medicinal cannabis, which was attributed to a reduction in their pain symptoms and led to an increased quality of life (Gruber et al., 2016). However, no studies have been conducted to date which have empirically evaluated the effect of cannabis use on cognitive-motor skills in EDS patients; thus, this study will be the first to compare these immediate effects in EDS to a large dataset of healthy legal users.
$5,000
Primary Investigator:
Ms. Holly Clayton
York University
Characterization of Vulvodynia and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders Pain in Females
Ehlers-Danlos syndromes (EDS) are a community of hereditary soft connective tissue disorders that include signs and symptoms of joint hypermobility, skin hyperextensibility and other skin texture differences, and fragility of internal organs, vessels and soft tissues.[1; 2] Hypermobility spectrum disorders (HSD) are a group of conditions with symptomatic joint hypermobility that do not fulfill the diagnostic criteria for hypermobility type EDS.[3] The separation between HSD and hEDS is unclear; therefore, many use a single label of EDS/HSD. 90% of individuals with EDS/HSD have chronic pain.[4] 77% of females with EDS have painful sexual intercourse (dyspareunia),[5-7] compared to 20% of females in the global population.[8; 9] Vulvodynia is chronic vulvar pain with dyspareunia.[10] Vulvodynia pain can be triggered by wearing clothing that contacts the vulva (external genitals) or by having vaginal sexual intercourse.[11] Pain from vulvodynia can be so severe that it can render sexual intercourse impossible and may drive women to have suicidal thoughts.[12-14] EDS/HSD and vulvodynia share several comorbid conditions that have been identified separately but the association between the two has never been reported.[15] Our preliminary research of 1146 females with EDS/HSD, found 50% of the participants had vulvodynia symptoms, over 6 times that of females in the general U.S. population (8%).[15] There is little research characterizing EDS/HSD pain (location, intensity, quality, and temporality) and no research characterizing vulvodynia in EDS/HSD. The purpose of our study is to characterize EDS/HSD pain and vulvodynia pain; and to identify patterns in pain presentation, for example, achy, intermittently, and mild pain vs. sharp, constant, and severe pain. Our study will also examine comorbid conditions (occurring together) in EDS/HSD and vulvodynia and identify if there is a relationship between the presence of comorbid conditions and pain presentation. We will examine generalized and vulvar pain in an online survey accessed via social media. We will recruit 825 females (275 with EDS/HSD only, 275 with vulvodynia only, and 275 with EDS/HSD and vulvodynia). Pain location, intensity, quality, and pattern will be measured with PAINReportIt®, a computerized tool used to characterize pain. The characterization of generalized and vulvar pain in females with EDS/HSD and/or vulvodynia will allow for identification of pain patterns and comorbid condition patterns as well as allow for the development of targeted treatment methods. Therefore, our aims are: Aim 1: Characterize pain patterns across the sensory aspect of pain (location, intensity, quality, and temporality) among females with EDS/HSD only, vulvodynia only, and EDS/HSD and vulvodynia. Aim 2: Characterize patterns of comorbid conditions experienced by females with EDS/HSD only, vulvodynia only, and EDS/HSD and vulvodynia, and determine how these patterns are associated with pain patterns. Females with and without EDS/HSD suffer from debilitating generalized and vulvar pain without effective treatment options.[3; 16; 17; 11] In order to know whom to target with which treatment strategies, it is critical to consider females’ experiences with pain and comorbid conditions holistically. This study provides a framework for developing personalized healthcare with the greatest impact for the treatment of millions living with chronic pain.
$5,000
Primary Investigator:
Dr. Jennifer Glayzer
University of Illinois Chicago
Molecular changes involved in Mast activation disease (MCAD) in patients with overlap hypermobile Ehlers-Danlos Syndrome (hEDS) and irritable bowel syndrome (IBS)
An effective treatment can be found; however, effective treatments are not always found. We aim to determine if patients with IBS/hEDSoverlap have a different mast cell profile in the gut lining compared to those with IBS without hEDS and healthy subjects. We will determine if there is a distinct symptom profile in patients with IBS/hEDS overlap which can improve recognition of this subgroup of patients. This will be the firMast cells are a type of white blood cell that are responsible for producing inflammatory reactions in response to detection of foreign particles in the body. They exist in both the gut lining (mucosa)as well as the connective tissue. Upon activation, mast cells release numerous chemicals which may result in inflammation in many bodily systems. Studies have shown an increase in mucosal mast cell counts in patients with Irritable Bowel Syndrome (IBS), particularly those with predominantly diarrhoea symptoms. Furthermore, it has been found that mast cells lie next to the nerves in the gut of IBS patients and this may result in tummy pain. Mast cells and Mast Cell Activation Disease (MCAD) have also been implicated in patients with hypermobile Ehlers Danlos Syndrome (hEDS).MCAD is defined as an elevated number or increased activity of mast cells, resulting in inflammatory reactions. Furthermore, an overlap between IBS and hEDS is now recognized with 54% of hEDS patients also meeting the criteria for IBS.
Although hEDS patients display signs of MCAD, with symptoms such as; itching, redness, diarrhea and tummy pain, there are no studies which have looked at alterations in the distribution and quantity of mast cells in the gut of hEDS patients and whether this correlates with IBS-like gastrointestinal symptoms, such as diarrhea and pain in the abdomen. Therefore, there are currently no management guidelines for gut symptoms in patients with MCAD and hEDS. Patients demonstrating gut manifestations of mast cell activation disease are poorly recognized and treated on the basis of presenting symptoms on a trial and error basis. This approach often leads to patients taking many medicines beforst large scale study to look at mast cells and other pro-inflammatory markers in the gut of patients with hEDS and may result in better understanding of the various inflammatory markers responsible for the symptoms of mast cell activation disease.
$5,000
Primary Investigator:
Miss Anisa Choudhary
Wingate Institute of Neurogastroenterology
Clinical features associated with mast cell disorders in patients with hypermobile Ehlers Danlos Syndrome
Recent years have seen numerous investigators recognize a ‘quirky’ association – which is that an immunological disorder of connective tissue elasticity. This grant aims to study this association in order to generate hypotheses regarding the mechanisms that cause abnormal immune responses, that then suggest new treatment options. We will recruit participants who have been diagnosed with hEDS, hypermobility disorders (HDS), and other forms of EDS as disease controls. A further group of controls, including participants, with disorders that involve mast cells in participants will be assessed for the presence of mast cell–related symptoms with a symptom questionnaire developed and validated for patients with macrocytosis.
$5,000
Primary Investigator:
Dr. Jeremy McComish
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.
$148,348.10
Primary Investigator:
Dr. Jared R Fletcher
Mount Royal University
4825 Mt Royal Gate SW,
Calgary, AB
T3E 6K6,
Canada
Headache disorders and craniocervical junction abnormalities in hypermobile Ehlers-Danlos Syndrome
BACKGROUND
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.
RESEARCH METHODS
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.
AIMS AND SIGNIFICANCE OF RESEARCH
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 the 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.
$99,159
Primary Investigator:
Dr. Ines Kapferer-Seebacher
Medical University of Innsbruck
Christoph-Probst-Platz 1,
Innrain 52 A, 6020 Innsbruck
Austria
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 generalized 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 currently 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.
$164,393.53
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 randomized controlled trial (RCT) (ClinicalTrials.gov identifier NCT03869307), we are investigating the effectiveness of a 16-week heavy strengthening exercise program 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 participants report pain before and after each exercise session, which makes it possible to analyze if pain decreases, increases, stays the same, and how it varies during the strengthening exercise program. 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 the salary for a research assistant, who will type in all data from the exercise diaries (approximately 100 participants) and help with the data analysis.
$5,000
Primary Investigator:
Mr. Behnam Liaghat
Syddansk Universitet(University af Southern Denmark]
Campusvej 55
5230 Odense M
Denmark
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 the 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 a 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, Ph.D. 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, the University of the West of England, Bristol, United Kingdom. The funding will cover travel expenses for the researchers and the included participants.
$5,000
Primary Investigator:
Mr. Behnam Liaghat
Syddansk Universitet(University af Southern Denmark]
Campusvej 55
5230 Odense M
Denmark
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.
$5,000
Primary Investigator:
Dr. Lies Rombaut
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,
Belgium
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 patients.
$5,000
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.
$5,000
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, diarrhea, 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 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 was 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 like 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 acknowledgment, 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 background.
$5,000
Primary Investigator:
Miss Inge De Wandele
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,
Belgium
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.
$5,000
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.
$5,000
Primary Investigator:
Dr. Delfien Syx
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
9000 Ghent,
Belgium
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
$5,000
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.
$5,000
Primary Investigator:
Dr. Rebecca Sorber
Johns Hopkins University School of Medicine
733 N Broadway,
Baltimore, MD 21205,
United States
Additional Research
Diet and EDS
Professor Qasim Aziz at Barts and The London School of Medicine and Dentistry has been caring for patients with EDS for many years. He has heard consistent stories of his patients’ symptoms improving with a change of diet. Some patients have improved a great deal and are living happy lives again. It’s now time to test, in a scientific study, whether changes in diet really can improve EDS symptoms in adults. Latest statistics from Professor Aziz’s London clinic show that, on average, EDS symptoms start at the age of 12 but the condition is not diagnosed until the age of 24.
hEDS is also associated with a range of gut disorders, including acid reflux and irritable bowel syndrome. There are no drugs that target connective tissue abnormality. Current treatments include medications to reduce symptoms, alongside physiotherapy for muscle and joint issues.
Good nutrition is essential for connective tissue repair and general healing. Certain nutrients are needed for the body to make collagen and support connective tissue function. Identifying specific nutrients needed for connective tissue function is important.
The Ehlers-Danlos Society and The Ehlers-Danlos Support UK fundraised together, jointly, towards research into Diet and EDS in 2018 and 2019. All donations made through The Ehlers-Danlos Society were transferred to The Ehlers-Danlos Support UK in 2020, who is managing a research study into Diet and EDS.
$7,997
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.
$50,000
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.
$75,000
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.
$75,000
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 (https://eds.gene.Ie.ac.uk) 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.
$75,000
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.
$69,020
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.
$1,000,000
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.
$5,000
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.
$5,000
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, the 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.
$5,000
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.
$5,000
Primary Investigator:
Dr Rubina Aktar
Queen Mary University of London
