To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.
The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.
There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.
These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.
(1) Neuromuscular Disease Foundation - payment for travel to the HIBM patient and board meeting
(1) Jain Foundation - I am a direct employee (VP of Clinical Strategies) of the Jain Foundation who is the funder of the study attributed in the manuscript
1. Member, External Adviosry Committee (EAC), NIH/NIDDK, Chronic Kidney Disease in Children, 2. Member, Pediatric Advisory Committee, FDA (end date 6/30/2017).
1. Department of Defense/USAMRAMC,W81XWH-04-1-0851, Dir Coord Ctr, 2008-2016 2. NIH/NINDS -NS045911, Statistician,2008- 2016 3. Dept of Defense/USAMRAA W81XWH-09-1-0592, Principal Investigator,2009 ? 2016 4. Dept of Education,H133B090001, Dir, Coord Ctr, 2009- 2016 5. NIH/NCATS-UL1RR031988 /UL1TR000075, Director of DEB Component, 2010-2015 6. NIH/NIAMS- AR061875, Dir. Coord Ctr 2011-2016 7. NIH/NIAMS - AR0623805, Dr. Coord Ctr 2011-2016 8. NIH/NICHD - HD040677, Core Assoc Dir, 2011-2016 9. NIH/NICHD - HD058567, Dir Coord Ctr, 2012-2017 10. Dept of Defense/USAMRAA, W81XWH-12-1-0417, 2012-2016, Principal Investigator 11. PCORI, 0057, 2013-2015. 12. Dept of Defense/USAMRAA, W81XWH-15-1-0508, 2015-2018, Dir of Coord Ctr.
(1) European Commission, 602485, PI, 2013-2017 (2) EPSRC, EP/L012189/1, PI, 2014-2017 (3) European Commission, 667078, co-I, 2016-2019
(1) UK Academy of Medical Sciences, 2012-2014 (2) Arthritis Research UK, 2012-2015 (3) Alzheimer's Society UK, 2014-2016
1 - Combined commercial and non-profit, 2012-2016; FOR-DMD evaluation of steroid dosing in Duchenne muscular dystrophy, Funded by NIH, PPMD, Marathon Pharmaceuticals; role: DSMB- chair.
1) Non-profit for myotonic dystrophy cognitive function in adolescents; from family benefactor 2) Non-profit for myotonic dystrophy genotype-phenotype correlations; from family benefactor
1) Cytokinetics, Inc. travel to NY, advisory meeting (2015) 2) Biogen, Inc. travel to Boston, advisory meeting (2015, 2016) 3) Roche, Inc. travel to Istanbul, investigators? meeting (2015) 4) Isis Pharamceuticals, travel to San Diego and Miami, investigators? meetings (2015) 5) Spinal Muscular Atrophy Foundation, travel to NY for annual conference (2015) 6) Parent's Project Muscular Dystrophy, travel to Washington, DC for advisory committee (2015) 7) Myotonic Dystrophy Foundation, travel to Washington, DC for advisory committee (2014, 2015, 2016) 8) American Association of Pediatrics, travel to conference and presentation honorarium (2014) 9) Myotonic Dystrophy Foundation, travel to Miami, FL (2016) 10) Biogen, SMA Advisory committee, travel to Rome, Italy (2015) 11) PPMD, DMD Scientific Advisory Committee, Tampa, FL (2016) 12) Carrel-Krusen Organization, Honoraria and Travel, Dallas, TX (2016)
(1) Patent on Myotonic Dystrophy type 2 genetic testing, licensed to Athena Diagnostics (2) Patent on Spinocerebellar Ataxia type 5 genetic testing, licensed to Athena Diagnostics
Stanford University, Departments of Neurology and Neuroscience, Pediatrics
1) Isis Pharmaceuticals ? Myotonic Dystrophy Advisor 2) Biogen, Inc. ? SMA Advisory Board 3) Cytokinetics, Inc. ? SMA Advisor 4) Sarepta Therapeutics ? Duchenne Advisor 5) PTC Therapeutics - Duchenne Advisor
(1) Genzyme Corporation, Site PI, 2008-2014 (2) Isis Pharmaceuticals ? SMA and myotonic dystrophy research, Site PI, 2013-2015 (3) Sarepta Pharmaceuticals? Duchenne muscular dystrophy research, Site PI, 2015 (4) Cytokinetics, Inc - SMA research, Overall PI, 2016 (5) Genzyme, Inc - Pompe research, Site PI, 2016 (6) BioMarin Pharma - Pompe research, Site PI, 2016
(1) Muscular Dystrophy Association, PI, 2011-2015 (2) Myotonic Dystrophy Foundation, PI, 2014-2015 (3) Spinal Muscular Atrophy Foundation, PI, 2015
(1) DM2 genetic testing, Athena Diagnostics, 2002-2015 (2) SCA5 genetic testing, Athena Diagnostics, 2007-2015
(1) German Duchenne parents project (2)IRDiRC Interdisciplinary Scientific Committee (3)German Muscular Dystrophy Network (4) Myotubular Trust Patient Registry (5) Action Duchenne Patient Registry (6) German Patient Registries on DMD and SMA
(1)PTC Therapeutics Inc, honorarium for lecture at satellite symposium ICNMD Nice 2014 and travel paid to Newcastle University (2)Ultragenyx Pharmaceutical Inc., travel
(1) Journal of Neuromuscular Diseases, Editor in Chief, 2014-current (2)Journal of Neurology, Editorial Board Member, 2007-current
(1)Roche Pharmaceuticals (paid to Newcastle University) (2)ASD Therapeutics Partners LLC (paid to Newcastle University) (3)IOS Press (paid to Newcastle University) (4)Alexion Pharmaceuticals Inc.(paid to Newcastle University) (5)Ultragenyx Pharmaceutical Inc.(paid to Newcastle University) (6) Fondazione Cariplo (paid to Newcastle University)
(1) Marigold Foundation Ltd (2)Ultragenyx Pharmaceutical Inc (3)PTC Therapeutics Inc (4)Eli Lilly and co (5)Action Benni & Co e.v (6)GSK (GlaxoSmithKline) (7)Trophos SA
(1)European Commission (RD-Connect), 305444, Coordinator, 2012-2018 (2) European Commission (OPTIMISTIC), 305697, co-investigator, 2012-2016 (3)European Commission (NeurOmics), 305121, co-investigator, 2012-2017 (4)Medical Research Council (MRC) G1002274, 98482, co-investigator, 2015-2016 (5)Medical Research Council (MRC), co-investigator, 2013-2018 (6)National Institute for Health Research (NIHR)PD00402, 2015-2017
(1)Action Duchenne, (2) Association Francaise Contre les Myopathies (3)British Heart Foundation (4)Muscular Dytrophy UK (5)National Cancer Institute (6) Spinal Muscular Atrophy Support UK (7)Wellcome Trust (8)Jennifer Trust (9)Duchenne Parent Project
1) Consultant to AveXis Therapeutics 2) Consultant to Serapta Therapeutics
1) Support for clinical trial sponsored by AveXis Therapeutics 2)Support for clinical trial sponsored bySerapta Therapeutics
MDA Clinical Research Network (MDA259206) Jesse's Journey
Received funding for travel and educational support from Genzyme
Received institutional support from the University of Padova for genetic research (1998-present)
Funded by Italian Telethon (2008-present) e by Italian Ministry of Health
Myositis Association: Travel reimbursement for visiting talks at University medical center Grand Rounds
(1) TS-HDS antibody 7,175,989, issued 2007; (2) GALOP antibody 6,121,004, issued 2000; (3) GM1 ganglioside antibody 6,077,681, issued 2000; (4) Sulfatide antibody 6,020,140, issued 1995
(1) Genzyme, (2) Insmed, (3) Knopp, (4) Ultragenyx, (5) Ionis, (6) Sanofi, (7) Cytokinetics, (8) GSK, (9) Biogen, (10) CSL Behring (11) Biomarin
(1) CINRG Children's Hospital Washington DC, Investigator 2007-2009; (2) Muscular Dystrophy Association, Investigator 2007-2009
(1) GALOP antibody 6,121,004, issued 2000; (2) GM1 ganglioside antibody 6,077,681, issued 2000; (3) Sulfatide antibody 6,020,140; issued 1995
(1)Pfizer, advisory board, for past 2 years (2)Italfarmaco S.p.A., advisory board, for past year (3)Audentes Therapeutics, advisory board, for past 2 years (4)Bristol-Myer Squibb, advisory board, for past year (5)Summit Therapeutics, advisory board, for past year (6)Tivorsan, advisory board, for past year (7)Gene therapy trial at Nationwide Children's Hospital, Ohio, US; Data Safety Monitoring Board
(1) Sanofi Genzyme, travel expenses and/or honoraria for lectures or educational activities related to Pompe disease and next generation sequencing.
(1) Neuromuscular Disorders, editorial board member, 6 years (2) Journal of Neuromuscular Diseases, editorial board, second year (3) PLOS Currents Muscular Dystrophy, Board of Reviewers, 3 year
(1)Sanofi Genzyme, clinical trial funding as UK chief investigator (2)BioMarin, clinic trial funding as UK chief investigator (3)Ionis Pharmceuticals, clinic trial funding as a principal investigator (4) Sarepta Therapeutics, clinical trial funding as a principal investigator (5) I have a research collaboration on a sequencing project funded by Ultragenyx and Sanofi Genzyme.
(1) Funding from the European Commission (2) Funding from the UK Medical Research Council
(1) funding from the Parent Project Muscular Dystrophy (2) funding from Association Francaise Contre les Myopathies (3) funding from the LGMD2I Research Fund (4) funding from the Wellcome Trust (5) funding from the Sylvia Aitken Charitable Trust (6) funding from Muscular Dystrophy UK (7) funding from Action Medical Research
(1) Myology Institute in Paris (2) National Center for Child Health and Development, Japan
(1) Japanese Society of Neurology, speaker honoraria (2) Pharmaceutical and Medical Device Regulatory Science Society of Japan, speaker honoraria (3) International Collaboration Forum of Human Gene Therapy for Genetic Disease, speaker honoraria (4) Japan Health Sciences Foundation, speaker honoraria (5) Jichi Medical University, speaker honoraria (6) MSD K.K., speaker honoraria (7) The Japan Society of Human Genetics, speaker honoraria (8) Chugai Pharmaceutical Co. Ltd., speaker honoraria (9) Eisai Co. Ltd, speaker honoraria
(1) J. Neuromuscular Diseases, Associate editor for reviews, 2013- (2) Am. J. Pathology, Associate editor, 2014- (3) Neuromuscular Disorders, Editorial board member, 2015-
(1) Antisense nucleic acid, sequence for exon 53 skip (2) Antisense nucleic acid, sequence for exon 44 skip (3) Antisense nucleic acid, sequence for exon 51 skip (4) Antisense nucleic acid, sequence for block skip
(1) Ono Pharmaceutical Co. Ltd. (2) Chugai Pharmaceutical Co. Ltd. (3) Taiho Pharma (4) Daiichisankyo Co. Ltd. (5) Takeda Pharmaceutical Co. Ltd.
(1) Taiho Pharma (2) GlaxoSmithKline K.K. (3) Nippon Shinyaku Co. Ltd. (4) TAKARA BIO INC. (5) JCR Pharmaceuticals Co., Ltd.
(1) Japan Agency for Medical Research and development (AMED), Practical Research Project for Rare /Intractable Diseases, #16ek0109154h0002, Principal Investigator, 2015-2018. (2) AMED, Practical Research Project for Rare/Intractable Diseases, #16ek0109169h0003, Principal Investigator, 2014-2017. (3) AMED, Promoting Clinical Trails for Development of New Drugs and Medical Devices, #16lk0201006h0005, Principal Investigator, 2012- 2017. (4) AMED, Research Center Network for Realization of Regenerative Medicine, Project for Technological Development, #16bm0404001h0004, Principal Investigator, 2013-2019. (5) AMED, Research Center Network for Realization of Regenerative Medicine, The Program for Intractable Diseases research utilizing Disease-specific iPS cells, 16bm0609005h0005, Site Investigator, 2013- 2018 (6) Ministry of Education, Sports, Science and Technology (MEXT), Grants-in-AId for Scientific Research (B), Principal Investigator, 2013- 2016.
(1) National Center of Neurology and Psychiatry (NCNP), Intramural Research Grant, #28-06, Principal Investigator, 2016-2019. (2) NCNP, Intramural Research Grant, #25-05, Principal Investigator, 2013-2016. (3) National Cerebral and Cardiovascular Center (4) National Center for Child Health and Development
(1) Novartis Pharma GmbH EU Local Advisory Board Meeting on April 15, 2013 on the topic of Sporadic Inclusion Body Myositis (sIBM), (2) Steering Committee for a Prospective Observational Study in Sporadic Inclusion Body Myositis (sIBM), RTI HS, July 2014, (3) Ataluren (Translarna?) Advisory Board Meeting, PTC Therapeutics, November 2014, (4) National Advisory Board Olesoxime ? SMA, Roche Pharma AG, December 2015, (5) Advisory Board Meeting sIBM, Novartis Pharma GmbH, February 2016, (6) Advisory Board Meeting Clinical Research in DMD, Gr?nenthal Pharma AG, February 2016 (7) SMA Advisory Board Meeting AveXIS, April 2016
(1) EMG Seminar, Vienna, Krankenhaus Hietzing mit NZ-Rosenhuegel, travel and speaker honoraria, April 2014 (2) BYM338B2203 EU Investigator Meeting, Novartis Pharma GmbH, travel and accommodation, February 2013 (3) Talk ?Update Muskeldystrophien?, Biogen Pharma GmbH, speaker honoraria, October 2013 (4) Talk ?Update sIBM?, Novartis Pharma GmbH, speaker honoraria
Consultancies from (1) Guidepoint Global, (2) GLG Consult and (3) Olson Research on the topic of muscular dystrophies, spinal muscular atrophy, myasthenia, LEMS and from (4) Novartis on the topic of IBM
(1) Glaxo Smith Kline GmbH, DMD BOI (2) Trophos AG (now Roche Pharma AG), SMA-TRO19622CLEQ1275-1 (3) Grifols GmbH, Gamedis Study (4) Novartis Pharma GmbH, IBM registry
Federal Ministry of Education and Research, Bonn, Germany, MD-NET 01GM0601, 2009-2013, and CMT-NET 01GM1511B, 2016-2019
(1) Jain Foundation, Dysferlinopathy Natural History Study, ongoing (2) Deutsche Gesellschaft f?r Muskelkranke, MFM patient registry, 04-2014 (2) Association contre les Myopathies (AFM) DdT2 2010 Funding Rech Translat ARD/SS/2010/2077/Following number 15037/CA 15/07/10 DRD10/PHYLO/DEPRE/MNCMT/ALLEM, CMT registry (3) Friedrich-Baur-GmbH, Burgkunstadt, ?Oberfrankenprojekte?, 12/11 - 12/16
Acceleron, AVI Biopharma, GSK, Genzyme, Prosensa, PTC, Santhera, ELIXER, BioMarin Pharmaceuticals (all moneys payable to Newcastle University).
Disorders of Voluntary Muscle 2010, Cambridge University Press. Ed Karpati, Hilton Jones, Bushby and Griggs
Newcastle University, Action Research Professor of Neuromuscular Genetics
See above (SABs) also Debiopharm, Lilly Pharmaceuticals, Summit Corporation, Insight Research Group, Galapagos SASU, Shire Human Genetics Therapies Inc., Amsterdam Molecular Therapeutics, European Neuromuscular Centre, Bristol-Meyers Squibb Company, Solid Ventures LLC
Trial support from PTC, AVI and Pfizer Global Research and Development
Grant support from Medical Research Council UK, The European Union, NIH, NHS England, US Department of Defence
Muscular Dystrophy Campaign, Association Francaise contre les myopathies, INC Research, Duchenne Children's Trust, British Heart Foundation, Duchenne Parent Support, Wellcome Trust, Muscular Dystrophy Group of GB, Parent Project Muscular Dystrophy
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the University of Newcastle.
Coinvestigators are listed at Neurology.org/ng.
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