et al,

Harms, Matthew

Moore, Ursula R

Pestronk, Alan

English

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Washington University School of Medicine Digital Commons@Becker Open Access Publications 11-1-2018 Teenage exercise is associated with earlier symptom onset in dysferlinopathy: A retrospective cohort study Ursula R Moore Matthew Harms Alan Pestronk et al Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs 1224 J Neurol Neurosurg Psychiatry November 2018 Vol 89 No 11PostScriptFigure 1 Risk of symptomatic disease and wheelchair use over time in dysferlinopathy. Graphs show the probability of remaining event free during the time under study using Cox proportional hazards regression. events are the onset of symptoms (A), the first time a wheelchair is used (B) and the need to use a wheelchair full time (C). Survival probabilities significantly different from exercise group 0 are marked with an asterisk (*). For first-time wheelchair use (B), this graph shows the results excluding those patients over 50 years of age at the screening visit as including these patients led to a violation of the proportional hazards assumption.Teenage exercise is associated with earlier symptom onset in dysferlinopathy: a retrospective cohort studyIntroductIonDysferlinopathy, an autosomal reces-sive muscular dystrophy caused by DYSF mutations, demonstrates a variable pheno-type and progression rate, with symptom onset ranging from first to eighth decade and some patients requiring wheelchairs for mobility within 10 years, with others remaining minimally affected.1Dysferlinopathy populations have previously been described as having an unusually high level of presymptomatic sporting ability.2 We hypothesised that this activity could be related to subse-quent disease progression and investi-gated the hypothesis using data from the Jain Foundation’s Clinical Outcomes Study (COS) of 202 patients with dysferlinopathy.1MethodSData were used from 182 of the 202 patients enrolled in the Jain COS; 10 dropped out and did not give permis-sion to use their data and 10 did not fully complete the exercise questionnaire.The questionnaire used in the screening visits (online supplementary informa-tion) between 6 November 2012 and 19 March 2015 asked about the type, level and frequency of all physical activity prior to symptom onset. Self-reported age of first symptoms, first wheelchair use and full-time wheelchair use was taken from screening questionnaires.Exercises were classified based on meta-bolic equivalents (METs) as moderate (MET 3–6) or vigorous (MET >6) (online supplementary table 1).3 Participants were coded, based on the maximum frequency of activity reported between ages 10 and 18 years, as 0—no physical activity; 1—vigorous activity occasionally/monthly, or moderate activity once weekly; 2— moderate activity multiple times per week or vigorous activity once weekly; and 3—vigorous activity multiple times per week.Statistical analysisAge of symptom onset was compared by analysis of variance (ANOVA) with least squares means for individual group differ-ences. Risk of symptom onset, occasional wheelchair use and full-time wheelchair requirement over time were compared for exercise groups 1, 2 and 3 against group 0 using Cox proportional hazards regres-sion. Proportional hazards assumption was violated for initial wheelchair use. Inspection of survival curves suggested this was occurring at later ages; thus, anal-ysis was rerun censoring at age 50 if there was no wheelchair use up to that point, which prevented violation of this assump-tion while capturing 46/55 events.Interaction between teen exercise level, gender and clinical diagnosis was also assessed by two-way ANOVA. Subgroups of limb girdle muscular dystrophy 2B (LGMD2B), Miyoshi myopathy (MM) or ‘other’ (all genetically confirmed dysferl-inopathies) were used for analysis.reSultSExercise group 0 had more female patients (65%). Demographic characteristics of each exercise group were otherwise similar (online supplementary table 2).Age of symptom onsetEstimated mean age of symptom onset differed by group (P=0.03) and was later in group 0 (mean 24.8 (95% CI 22.3 to 27.2)) compared with groups 2 (20.2 (18.1 to 22.3), P=0.006) and 3 (20.6 (18.4 to 22.8), P=0.01), but not 1 (21.7 (17.7 to 25.7), P=0.20). Cox regression analysis suggested that groups 2 (HR 1.56 (95% CI 1.06 to 2.30)) and 3 (HR 1.54 (1.04 to 2.30)) were at increased risk of earlier symptom onset than group 0 (figure 1). This was not significant for group 1 (HR 1.38 (0.78 to 2.45)).In patients with a clinical diagnosis of LGMD2B, groups 1–3 all showed a significantly increased risk of earlier onset compared with group 0 (1: HR 7.74 (95% CI 3.07 to 19.49); 2: HR 1.71 (1.05 to 2.77); 3: HR 1.91 (1.14 to 3.18)). Signifi-cant associations were not seen among those with a diagnosis of MM or ‘other’.School of Medicine Library &. Protected by copyright. on February 26, 2020 at Washington Universityhttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2017-317329 on 29 January 2018. Downloaded from 1225J Neurol Neurosurg Psychiatry November 2018 Vol 89 No 11PostScriptResults were independent of gender, which was not significantly related to age of onset (P=0.329) or exercise group (P=0.328).Wheelchair useFifty-five patients reported age at first wheelchair use and 42 using a wheelchair full time.Statistical analysis showed a higher risk for part-time wheelchair use in exer-cise groups 2 (HR 3.57 (95% CI 1.36 to 9.36)) and 3 (HR 5.44 (2.20 to 13.48)) compared with group 0; no association was noted for group 1 (HR 2.12 (0.53 to 8.51)).Greater teenage activity was also asso-ciated with increased risk of full-time wheelchair requirement in group 3 (HR 4.11 (1.75 to 9.64)). This was not signifi-cant in groups 1 (HR 0.97 (0.20 to 4.73)) or 2 (HR 2.18 (0.82 to 5.75)).dIScuSSIonIn the present study, patients recalling greater teenage exercise levels demonstrated increased risk for earlier symptom onset and wheelchair requirement. Teenage exercise level was chosen as this is typically before symptom onset in dysferlinopathy, yet old enough for significant exercise regimens to have started. Although an association between exercise and subsequent disease progression has previously been suggested by Angelini et al4 Klinge et al2 reported no significant effect of exercise on age of symptom onset in 36, mostly LGMD2B, patients. These studies all rely on patient recall, introducing potential question and recall bias. We tried to mitigate for this using a scoring system based on METs rather than Klinge’s use of patient-reported sporting level. However, our approach still does not produce uniform exercise catego-ries, requiring grouping of different types and frequencies of exercise, which may not have equitable physiological impact. Unfor-tunately, this is the nature of a retrospec-tive study, which is necessary while so few patients are diagnosed presymptomatically.Exercise is usually considered beneficial in muscular dystrophies, and so this finding in dysferlinopathy may suggest a unique underlying pathological mechanism. Inves-tigation of this was not within the scope of this study. However, previous work has suggested that dysferlinopathy may increase aptitude for training early in life, but the more a patient exercises vigorously, the more muscle damage occurs, which is then inadequately repaired5—accelerating both disease onset and symptom progression.This study raises implications for patients and families. If intensive exercise causes earlier onset and faster progression, asymptomatic patients should consider limiting their exercise and affected siblings should be identified to allow for early disease-modifying advice. However, as the HRs are small, this needs to be balanced against the loss of other lifestyle benefits of exercise. As we did not look at the effects of exercise once symptoms began, we would not advocate that symptomatic patients stop exercising.This letter describes an association of intensive exercise during the teenage years with earlier disease onset and faster rate of disease progression in patients with dysferlinopathy.ursula r Moore,1 Marni Jacobs,2,3 roberto Fernandez-torron,1,4 Jiji Jang,2,3 Meredith K James,1 Anna Mayhew,1 laura rufibach,5 Plavi Mittal,5 Michelle eagle,1 Avital cnaan,3,6 Pierre G carlier,7 Andrew Blamire,8 heather hilsden,1 hanns lochmüller,1 ulrike Grieben,9 Simone Spuler,9 carolina tesi rocha,10 John W day,10 Kristi J Jones,11 diana X Bharucha-Goebel,12,13 emmanuelle Salort-campana,14 Matthew harms,15 Alan Pestronk,15 Sabine Krause,16 olivia Schreiber-Katz,16 Maggie c Walter,16 carmen Paradas,17 Jean-Yves hogrel,18 tanya Stojkovic,18 Shin’ichi takeda,19 Madoka Mori-Yoshimura,19 elena Bravver,20 Susan Sparks,20 Jordi diaz-Manera,21,22 luca Bello,23 claudio Semplicini,23 elena Pegoraro,23 Jerry r Mendell,24 Kate Bushby,1 Volker Straub11The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle upon Tyne, UK2Children’s Research Institute, Division of Biostatistics and Study Methodology, Children’s National Health System, Washington, District of Columbia, USA3Department of Pediatrics, epidemiology and Biostatistics, George Washington University, Washington, District of Columbia, USA4Neuromuscular Area, Biodonostia Health Research Institute, Neurology Service, Donostia University Hospital, Donostia-San Sebastian, Spain5The Jain Foundation, Seattle, Washington, USA6Children’s Research Institute, Division of Biostatistics and Study Methodology, Children’s National Health System, Washington, District of Columbia, USA7AIM and CeA NMR Laboratory, Institute of Myology, Pitié-Salpêtrière University Hospital, Paris, France8Magnetic Resonance Centre, Institute for Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK9Charite Muscle Research Unit, experimental and Clinical Research Center, The Max Delbrück Center for Molecular Medicine, Berlin, Germany10Department of Neurology and Neurological Sciences, School of Medicine, Stanford University, Stanford, California, USA11Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia12Department of Neurology, Children’s National Health System, Washington, District of Columbia, USA13National Institutes of Health (NINDS), Bethesda, Maryland, USA14Department of Neuromuscular and ALS Center, La Timone Hospital, Aix-Marseille Université, Marseille, France15Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA16Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University of Munich, Munich, Germany17Neuromuscular Unit, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, Spain18Institut de Myologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Boulevard de l’Hôpital, Paris, France19Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan20Carolinas Healthcare System Neurosciences Institute, Charlotte, North Carolina, USA21Centro de Investigación Biomédica en Red en enfermedades Raras (CIBeReR), Barcelona, Spain22Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain23Department of Neuroscience, University of Padova, Padova, Italy24Nationwide Children’s Hospital, Columbus, Ohio, USAcorrespondence to Professor Volker Straub, The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle upon Tyne Ne1 3BZ, UK;  volker. straub@ ncl. ac. ukcontributors URM: design and conception of this paper, analysis, interpretation, drafting, revising. MJ: design and conception of this paper, analysis, interpretation, drafting, revising. RF-T: design and conception of this paper, analysis, interpretation, drafting, revising. JJ: analysis, interpretation, revising. MKJ: acquisition of data, analysis, interpretation, drafting, revising. AM: acquisition of data, analysis, interpretation, drafting, revising, design of whole study, final approval. LR: drafting, revising, design of whole study, final approval. PM: revising, design of whole study, final approval. Me: acquisition of data, revising, design of whole study, final approval. AC: revising, design of whole study, final approval. PC: revising, design of whole study, final approval. AB: revising, design of whole study, final approval. HH: analysis, acquisition of data, interpretation, drafting, revising, final approval. HL: revising, design of whole study, final approval. UG: acquisition of data, revising, design of whole study, final approval. SS: acquisition of data, revising, design of whole study, final approval. CTR: acquisition of data, revising, design of whole study, final approval. JWD: acquisition of data, revising, design of whole study, final approval. KJJ: acquisition of data, revising, design of whole study, final approval. DXB-G: acquisition of data, revising, design of whole study, final approval. eS-C: acquisition of data, revising, design of whole study, final approval. MH: acquisition of data, revising, design of whole study, final approval. AP: acquisition of data, revising, design of whole study, final approval. SK: acquisition of data, revising, design of whole study, final approval. OS-K: acquisition of data, revising, design of whole study, final approval. MCW: acquisition of data, revising, design of whole study, final approval. CP: acquisition of data, revising, design of whole study, final approval. J-YH: acquisition of data, revising, design of whole study, final approval. TS: acquisition of data, revising, design of whole study, final approval. ST: acquisition of data, revising, design of whole study, final approval. MM-Y: acquisition of data, revising, design of whole study, final approval. eB: acquisition of data, revising, design of whole study, final approval. SS: acquisition of data, revising, design of whole study, final approval. JD-M: acquisition of data, revising, design of whole study, final approval. LB: acquisition of data, revising, design of whole study, final approval. CS: acquisition of data, revising, design School of Medicine Library &. Protected by copyright. on February 26, 2020 at Washington Universityhttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2017-317329 on 29 January 2018. Downloaded from 1226 J Neurol Neurosurg Psychiatry November 2018 Vol 89 No 11PostScriptof whole study, final approval. eP: acquisition of data, revising, design of whole study, final approval. JRM: acquisition of data, revising, design of whole study, final approval. KB: design and conception of whole study, study design, acquisition of data, revising, design of whole study, final approval. VS: study design, revising, design of whole study, acquisition of data, final approval, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.Funding The Jain Foundation has provided an estimated US$4 million to fund this study. MRC funding of the John Walton Muscular Dystrophy Centre also supports this work. (Grant number MR/LK000608/1).disclaimer The views expressed in this submission are the authors’ own and not the official position of their institutions or funding bodies. competing interests None declared.ethics approval NReS Committee North east—Newcastle and North Tyneside 2. The trial was also registered at  ClinicalTrials. gov (NCT01676077).Provenance and peer review Not commissioned; externally peer reviewed.open access This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http:// creativecommons. org/ licenses/ by/ 4. 0/© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. ► Additional material is published online only. To view please visit the journal online (http:// dx. doi. org/ 10. 1136/ jnnp- 2017- 317329).to cite Moore UR, Jacobs M, Fernandez-Torron R, et al. J Neurol Neurosurg Psychiatry 2018;89:1224–1226.Received 26 September 2017Revised 5 December 2017Accepted 27 December 2017Published Online First 29 January 2018J Neurol Neurosurg Psychiatry 2018;89:1224–1226.doi:10.1136/jnnp-2017-317329RefeRences 1 Harris e, Bladen CL, Mayhew A, et al. The clinical outcome study for dysferlinopathy: an international multicenter study. Neurol Genet 2016;2:e89. 2 Klinge L, Aboumousa A, eagle M, et al. New aspects on patients affected by dysferlin deficient muscular dystrophy. J Neurol Neurosurg Psychiatry 2010;81:946–53. 3 U.S. Department of Health and Human Services PHS, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Nutrition and Physical Activity. Promoting physical activity: a guide for community action—general physical activities defined by level of intensity: Human Kinetics, 1999. 4 Angelini C, Peterle e, Gaiani A, et al. Dysferlinopathy course and sportive activity: clues for possible treatment. Acta Myol 2011;30:127–32. 5 Begam M, Galen SS, Roche JA. exhaustion of regenerative potential due to a low threshold for exercise-induced myogenesis might explain progressive weakness in dysferlin-linked muscle diseases. FASEB J 2016;30(Suppl 1):lb716.School of Medicine Library &. Protected by copyright. on February 26, 2020 at Washington Universityhttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2017-317329 on 29 January 2018. Downloaded from 

Teenage exercise is associated with earlier symptom onset in dysferlinopathy: A retrospective cohort study

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Teenage exercise is associated with earlier symptom onset in dysferlinopathy: A retrospective cohort study

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