Topological regulation of the estrogen transcriptional response by ZATT-mediated inhibition of TOP2B activity.

Human type-II topoisomerases, TOP2A and TOP2B, remove transcription associated DNA supercoiling, thereby affecting gene-expression programs, and have recently been associated with 3D genome architecture. Here, we study the regulatory roles of TOP2 paralogs in response to estrogen, which triggers an acute transcriptional induction that involves rewiring of genome organization. We find that, whereas TOP2A facilitates transcription, as expected for a topoisomerase, TOP2B limits the estrogen response. Consistent with this, TOP2B activity is locally downregulated upon estrogen treatment to favor the establishment and stabilization of regulatory chromatin contacts, likely through an accumulation of DNA supercoiling. We show that estrogen-mediated inhibition of TOP2B requires estrogen receptor α (ERα), a non-catalytic function of TOP2A, and the action of the atypical SUMO-ligase ZATT. This mechanism of topological transcriptional-control, which may be shared by additional gene-expression circuits, highlights the relevance of DNA topoisomerases as central actors of genome dynamics.

Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Generalized Hypermobility Spectrum Disorder: Protocol for a Pilot and Feasibility Randomized Controlled Trial.

BACKGROUND: Dyspnea is a prevalent symptom in individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and generalized hypermobility spectrum disorder (G-HSD), yet its contributors have not been identified. One known contributor to dyspnea is respiratory muscle weakness. The feasibility and effectiveness of inspiratory muscle training (IMT) in combination with standard-of-care rehabilitation (aerobic, resistance, neuromuscular stabilization, and balance and proprioception exercises) in improving respiratory muscle strength and patient-reported outcomes in patients with hEDS or G-HSD have not been evaluated. OBJECTIVE: This study aims to evaluate dyspnea, respiratory muscle strength, and patient-reported outcome measures (PROMs) in hEDS or G-HSD compared with healthy controls and to assess the feasibility of a randomized controlled trial of IMT and standard-of-care rehabilitation for improving respiratory muscle strength, exercise capacity, and PROMs compared with standard-of-care rehabilitation in hEDS and G-HSD. METHODS: The study will include 34 participants with hEDS or G-HSD and 17 healthy, age- and sex-matched controls to compare respiratory muscle structure and function and PROMs. After baseline assessments, participants with hEDS or G-HSD will be randomized into the intervention group and provided IMT combined with Ehlers-Danlos Syndrome standard-of-care rehabilitation or into the usual care group, and provided only standard-of-care rehabilitation for 8 weeks. The intervention group will be prescribed IMT in their home environment using the POWERbreathe K5 IMT device (POWERbreathe International Ltd). IMT will comprise 2 daily sessions of 30 breaths for 5 days per week, with IMT progressing from 20% to 60% of the baseline maximal inspiratory pressure (MIP) over an 8-week period. Feasibility will be assessed through rates of recruitment, attrition, adherence, adverse events, and participant satisfaction. The primary pilot outcome is MIP change over an 8-week period in hEDS or G-HSD. Secondary outcomes will include the evaluation of dyspnea using Medical Research Council Scale and 18-point qualitative dyspnea descriptors; diaphragmatic thickening fraction using ultrasound; respiratory muscle endurance; pulmonary function; prefrontal cortical activity using functional near-infrared spectroscopy; aerobic capacity during cardiopulmonary exercise testing; quality of life using Short Form-36; and scores from the Depression, Anxiety, and Stress scale-21. These measures will also be performed once in healthy controls to compare normative values. Multivariable regression will be used to assess the contributors to dyspnea. Paired 2-tailed t tests will be used to assess the changes in MIP and secondary measures after 8 weeks of IMT. RESULTS: Study recruitment began in August 2021 and, with several disruptions owing to COVID-19, is expected to be completed by December 2023. CONCLUSIONS: This study will provide a better understanding of the factors associated with dyspnea and the feasibility and effectiveness of IMT combined with standard-of-care rehabilitation. IMT may be a novel therapeutic strategy for improving respiratory muscle function and patient-reported outcomes in individuals with hEDS or G-HSD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04972565; https://clinicaltrials.gov/ct2/show/NCT04972565. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44832.

Exercise and Rehabilitation in People With Ehlers-Danlos Syndrome: A Systematic Review.

Objective: To conduct a systematic review examining the effect of exercise and rehabilitation in people with Ehlers-Danlos syndrome (EDS). Data Sources: The following databases were systematically searched: MEDLINE, MEDLINE In-Process/ePubs, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and Cumulative Index to Nursing and Allied Health. The final time point captured by the search is November 27, 2020. Study Selection: Eligible study designs included case-control, case-series, prospective cohort, retrospective cohort, and intervention studies of structured exercise or rehabilitation interventions. Eligible populations included adults (18 years or older) with EDS (all subtypes) and hypermobility spectrum disorders. The search was restricted to articles published in English. Data Extraction: Data were extracted by 2 independent reviewers. Risk of bias was assessed using the Physiotherapy Evidence Database (PEDro) scale for randomized controlled trials (RCTs) and Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) for non-RCTs. Reporting quality of RCTs was assessed using the Consolidated Standards for Reporting of Trials statement with the harms extension. Reporting was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Data Synthesis: The search yielded 10 eligible studies including 330 participants. The study designs included 5 RCTs, 1 cohort, 2 single-arm interventions, 1 retrospective, and 1 feasibility study. All studies showed some improvement in a physical and/or psychological outcome after the intervention period. One adverse event (nonserious) potentially related to the intervention was reported. Of the 5 RCTs, 2 were rated as high quality with low risk of bias using PEDro, and the majority of non-RCTs were rated as critical risk of bias by ROBINS-I. Conclusions: The results suggest that exercise and rehabilitation may be beneficial for various physical and psychological outcomes. Adequately powered and rigorous RCTs of exercise and rehabilitation interventions for people with EDS are needed.

The GoodHope Ehlers Danlos Syndrome Clinic: development and implementation of the first interdisciplinary program for multi-system issues in connective tissue disorders at the Toronto General Hospital.

Ehlers-Danlos Syndrome (EDS) are a heterogeneous group of genetic connective tissue disorders, and typically manifests as weak joints that subluxate/dislocate, stretchy and/or fragile skin, organ/systems dysfunction, and significant widespread pain. Historically, this syndrome has been poorly understood and often overlooked. As a result, people living with EDS had difficulty obtaining an accurate diagnosis and appropriate treatment, leading to untold personal suffering as well as ineffective health care utilization. The GoodHope EDS clinic addresses systemic gaps in the diagnosis and treatment of EDS. This paper describes a leap forward-from lack of awareness, diagnosis, and treatment-to expert care that is tailored to meet the specific needs of patients with EDS. The GoodHope EDS clinic consists of experts from various medical specialties who work together to provide comprehensive care that addresses the multi-systemic nature of the syndrome. In addition, EDS-specific self-management programs have been developed that draw on exercise science, rehabilitation, and health psychology to improve physical and psychosocial wellbeing and overall quality of life. Embedded into the program are research initiatives to shed light on the clinical presentation, underlying mechanisms of pathophysiology, and syndrome management. We also lead regular educational activities for community health care providers to increase awareness and competence in the interprofessional management of EDS beyond our doors and throughout the province and country.

A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders.

BACKGROUND: Ehlers-Danlos Syndromes (EDS) and Hypermobility Spectrum Disorders (HSD) are a heterogeneous group of heritable genetic connective tissue disorders with multiple characteristics including joint hypermobility, tissue fragility, and multiple organ dysfunction. Respiratory manifestations have been described in EDS patients, but have not been systematically characterized. A narrative review was undertaken to describe the respiratory presentations and management strategies of individuals with EDS and HSD. METHODS: A broad literature search of Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL was undertaken from inception to November 2020 of all study types, evaluating EDS/ HSD and pulmonary conditions. This narrative review was limited to adult patients and publications in English. RESULTS: Respiratory manifestations have generally been described in hypermobile EDS (hEDS), classical and vascular EDS subtypes. Depending on EDS subtype, they may include but are not limited to dyspnea, dysphonia, asthma, sleep apnea, and reduced respiratory muscle function, with hemothorax and pneumothorax often observed with vascular EDS. Respiratory manifestations in HSD have been less frequently characterized in the literature, but exertional dyspnea is the more common symptom described. Respiratory symptoms in EDS can have an adverse impact on quality of life. The respiratory management of EDS patients has followed standard approaches with thoracotomy tubes and pleurodesis for pleural manifestations, vocal cord strengthening exercises, continuous positive pressure support for sleep apnea, and exercise training. Reduced respiratory muscle function in hEDS patients responds to inspiratory muscle training. CONCLUSION: Respiratory symptoms and manifestations are described in EDS and HSD, and have generally been managed using conservative non-surgical strategies. Research into the prevalence, incidence and specific respiratory management strategies in EDS and HSD is needed to mitigate some of the associated morbidity.

The GoodHope Exercise and Rehabilitation (GEAR) Program for People With Ehlers-Danlos Syndromes and Generalized Hypermobility Spectrum Disorders.

Introduction: The Ehlers-Danlos Syndromes (EDS) and Generalized Hypermobility Spectrum Disorders (G-HSD) comprise a heterogeneous group of genetic disorders of abnormal synthesis and/or maturation of collagen and other matricellular proteins. EDS is commonly characterized by manifestations such as multi joint hypermobility that can lead to musculoskeletal pains, subluxations and dislocations, fragile skin, organ dysfunction, and chronic significant diffuse pain with fatigue, deconditioning eventuating to poor quality of life. Evidence suggests exercise and rehabilitation interventions may ameliorate symptoms of unstable joints, recurrent subluxations/dislocations, and chronic widespread musculoskeletal pain. To date, there have only been a few reports describing exercise and rehabilitation care strategies for people with EDS. Methods: In this manuscript, we describe the GoodHope Exercise and Rehabilitation (GEAR) program, its overarching principles, as well as the program development and delivery model. The GEAR program aims to decrease functional impairment, reduce pain, increase confidence in symptom self-management, and provide a community of support for people with EDS/G-HSD. To achieve these goals, we detail the model of care that includes exercise and rehabilitation therapy, education for self-management, and support accessing relevant community resources. Strengths and Limitations of the Study: GEAR represents a novel exercise and rehabilitation care model for people with G-HSD and various clinical EDS subtypes, beyond the commonly included hEDS subtype. Systematic collection of data via validated measurements is ongoing and will guide the refinement of GEAR and support the development of emerging exercise and rehabilitation programs for people with EDS.