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.
Marina Colombi, PhD
Full Professor of Medical Genetics
Department of Molecular and Translational Medicine Institution
University of Brescia
Viale Europa, 11 – 25123
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.
Sherene Shalhub, MD, PhD, and Peter Byers, MD
University of Washington
1959 NE Pacific Street
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
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.
Fransiska Malfait MD, PhD
Senior Clinical Investigator, Head of Clinic Department
Center for Medical Genetics Institution: Ghent University
Corneel Heymanslaan 10
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.
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.
Christina M. Laukaitis, MD, PhD, FACP, FACMG
Director, Genetic Consultation and Counseling Services, UAHS Center for Applied Genetics and Genomic Medicine
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.
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.
Leslie Russek, PT, DPT, PhD, OCS
Physical Therapy Department
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.
Verity Pacey B App Sci (Phty), PhD
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.
Leder af specialtandlægeuddannelsen i Ortodonti
Specialtandlæge i Ortodonti, ph.d., dr.odont
Det Sundhedsvidenskabelige Fakultet
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.
Dr Rubina Aktar
Queen Mary University of London