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Neuromuscular
Original research
Genotype–phenotype correlations in valosin-containing protein disease: a retrospective muticentre study
  1. Marianela Schiava1,
  2. Chiseko Ikenaga2,
  3. Rocío Nur Villar-Quiles3,
  4. Marta Caballero-Ávila4,
  5. Ana Topf5,
  6. Ichizo Nishino6,
  7. Virginia Kimonis7,
  8. Bjarne Udd8,9,
  9. Benedikt Schoser10,
  10. Edmar Zanoteli11,
  11. Paulo Victor Sgobbi Souza12,
  12. Giorgio Tasca13,
  13. Thomas Lloyd2,
  14. Adolfo Lopez-de Munain14,
  15. Carmen Paradas15,16,17,
  16. Elena Pegoraro18,
  17. Aleksandra Nadaj-Pakleza19,
  18. Jan De Bleecker20,
  19. Umesh Badrising21,
  20. Alicia Alonso-Jiménez22,
  21. Anna Kostera-Pruszczyk23,
  22. Francesc Miralles24,
  23. Jin-Hong Shin25,
  24. Jorge Alfredo Bevilacqua26,27,
  25. Montse Olivé28,29,30,
  26. Matthias Vorgerd31,
  27. Rudi Kley32,
  28. Stefen Brady33,
  29. Timothy Williams34,
  30. Cristina Domínguez-González35,36,
  31. George K Papadimas37,
  32. Jodi Warman-Chardon38,
  33. Kristl G Claeys39,40,
  34. Marianne de Visser41,
  35. Nuria Muelas35,42,43,
  36. Pascal LaForet44,
  37. Edoardo Malfatti45,
  38. Lindsay N Alfano46,47,
  39. Sruthi S Nair48,
  40. Georgios Manousakis49,
  41. Hani A Kushlaf50,
  42. Matthew B Harms51,
  43. Christopher Nance52,
  44. Alba Ramos-Fransi53,
  45. Carmelo Rodolico54,
  46. Channa Hewamadduma55,
  47. Hakan Cetin56,
  48. Jorge García-García57,
  49. Endre Pál58,
  50. Maria Elena Farrugia59,
  51. Phillipa J Lamont60,
  52. Colin Quinn61,
  53. Velina Nedkova-Hristova62,
  54. Stojan Peric63,
  55. Sushan Luo64,65,
  56. Anders Oldfors66,
  57. Kate Taylor67,
  58. Stuart Ralston68,
  59. Tanya Stojkovic3,
  60. Conrad Weihl69,
  61. Jordi Diaz-Manera1,70 VCP International Study Group
  62. VCP International Study Group
    1. 1John Walton Muscular Dystrophy Research Centre, Newcastle University, and Newcastle Hospitals NHS Foundation Trusts, Newcastle Upon Tyne, UK
    2. 2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    3. 3APHP, Centre de référence des maladies neuromusculaires, Institut de Myologie, Sorbonne Université, APHP, Hôpital Pitié-Salpêtrière, Paris, France
    4. 4Neuromuscular Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    5. 5Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle University, Newcastle upon Tyne, UK
    6. 6Department of Neuromuscular Research, National Institute of Neuroscience National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
    7. 7Department of Pediatrics Division of Genetics and Genomic Medicine, University of California-Irvine Medical Center Children’s Hospital of Orange County, Orange, California, USA
    8. 8Tampere Neuromuscular Center, Tampere University Hospital, Tampere, Finland
    9. 9Folkhalsan Genetic Institute, Helsinki University, Helsinki, Finland
    10. 10Department of Neurology, Friedrich-Baur-Institute Ludwig Maximilian University Clinics, Munich, Germany
    11. 11Department of Neurology, School of Medicine, Universidade de São Paulo (FMUSP), São Paulo, Brazil
    12. 12Disciplina de Neurologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
    13. 13Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy
    14. 14Biodonostia Neurosciences Area Group of Neuromuscular Diseases Biodonostia-Osakidetza Basque Health Service, San Sebastian, Spain
    15. 15Neurology Department, Neuromuscular Disorders Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain
    16. 16Instituto de Biomedicina de Sevilla, Sevilla, Spain
    17. 17Center for Biomedical Network Research on Neurodegenerative Disorders (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
    18. 18Department of Neurosciences, University of Padova, Padova, Italy
    19. 19Department of Neurology, Centre de Reference des Maldies Neuromusculaires Nord-Est-Ile de France, University Hospital of Strasbourg, Strasbourg, France
    20. 20Department of Neurology and Neuromuscular Reference Center, Ghent University Hospital, Ghent, Belgium
    21. 21Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
    22. 22Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital, Universiteit Antwerpen, Instituut Born Bunge, Antwerpen, Belgium
    23. 23Department of Neurology, Medical University of Warsaw, European Reference Network ERN-NMD, Warsaw, Poland
    24. 24Department of Neurology, Unitat de Patologia Neuromuscular i Gabinet d'electrodiagnòstic, Hospital Universitari Son Espases, Palma de Mallorca, Spain
    25. 25Laboratory of Molecular Neurology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
    26. 26Unidad Neuromuscular, Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Santiago de Chile, Chile
    27. 27Departamento de Neurología y Neurocirugía Clínica, Clínica Dávila, Santiago Chile, Chile
    28. 28Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
    29. 29Deaprtment of Neurology, Neuromuscular Disorders Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    30. 30Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
    31. 31Heimer Institut for Muscle Research, Klinikum Bergmannsheil, Ruhr University, Bochum, Germany
    32. 32Department of Neurology and Clinical Neurophysiology, St Marien-Hospital Borken, Borken, Germany
    33. 33Neurology Department, John Radcliffe Hospital, Oxford, UK
    34. 34Newcastle Motor Neurone Disease Care Centre, Royal Victoria Infirmary, Newcastle, UK
    35. 35Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain
    36. 36Neurology Service, Hospital Universitario 12 de Octubre, Madrid, Spain
    37. 37First Department of Neurology, Medical School, Eginition Hospital and National and Kapodistrian University of Athens, Athens, Greece
    38. 38Department of Medicine, Ottawa Neuromuscular Centre, Ottawa Hospital, Ottawa, Ontario, Canada
    39. 39Department of Neurology, University Hospitals Leuven, Leuven, Belgium
    40. 40KU Leuven Laboratory for Muscle Diseases and Neuropathies, Leuven, Belgium
    41. 41Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands
    42. 42Neuromuscular Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
    43. 43Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
    44. 44Neurology department, Raymond-Poincaré hospital, APHP, UVSQ, Paris-Saclay University, Paris, France
    45. 45APHP, Neuromuscular Reference Center Nord-Est-Ile-de-France, Henri Mondor Hospital, Université Paris Est, U955, INSERM, Créteil, IMRB, Paris, France
    46. 46Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
    47. 47Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA
    48. 48Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
    49. 49Department of Neurology, University of Minnesota Hospital, Minneapolis, Minnesota, USA
    50. 50Department of Neurology & Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA
    51. 51NewYork Presbyterian Columbia University Irving Medical Centre, New York, New York, USA
    52. 52Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa, Iowa, USA
    53. 53Neuromuscular Unit, Neurology Department, Hospital Germas Trias i Pujol, Badalona, Spain
    54. 54Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
    55. 55Sheffield Institute for translational neurosciences (SITRAN), Neuroscience Institute, University of Sheffield, Sheffield, UK
    56. 56Department of Neurology, Medical University of Vienna, Vienna, Austria
    57. 57Neurology Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
    58. 58Department of Neurology, University of Pécs, Pécs, Hungary
    59. 59Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
    60. 60Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia
    61. 61Neuromuscular Division, Neurology Department, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    62. 62Neurology Department, Bellvitge University Hospital, Bellvitge, Spain
    63. 63Neurology Clinic, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
    64. 64Department of Neurology, Huashan Hospital Fudan University, Shanghai, China
    65. 65National Center for Neurological Disorders, Shanghai, China
    66. 66Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
    67. 67Southern General Hospital, Glasgow, UK
    68. 68Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
    69. 69Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
    70. 70Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    1. Correspondence to Professor Jordi Diaz-Manera, John Walton Muscular Dystrophy Research Centre, Newcastle Hospitals NHS Foundation Trusts, Newcastle University, NE1 7RU, UK; jordi.diaz-manera{at}newcastle.ac.uk

    Abstract

    Background Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget’s disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype–phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype–phenotype correlations.

    Methods Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene.

    Results Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death.

    Conclusion This study expands the knowledge on the phenotypic presentation, natural history, genotype–phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

    • MUSCLE DISEASE
    • GENETICS
    • MYOPATHY
    • INCL BODY MYOSITIS
    • FRONTOTEMPORAL DEMENTIA

    Data availability statement

    Data are available from the corresponding author on reasonable request.

    https://doi.org/10.1136/jnnp-2022-328921

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      Data availability statement

      Data are available from the corresponding author on reasonable request.

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      Footnotes

      • Twitter @NA, @querques2000

      • Correction notice Since this article was first published, the author Jodi Warman has been updated to Jodi Warman-Chardon.

      • Collaborators VCP International Study Group: Adolfo López de Munain, Biodonostia Neurosciences Area Group of Neuromuscular Diseases Biodonostia-Osakidetza Basque Health Service, San Sebastián, Spain; Alba Ramos-Fransi, Neuromuscular Unit, Neurology Department, Hospital Germas Trias i Pujol, Spain; Aleksandra Nadaj-Pakleza, Centre de Reference des Maldies Neuromusculaires Nord-Est-Ile de France, Department of Neurology, University Hospital of Strasbourg, France; Alicia Alonso-Jiménez, Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital, Universiteit Antwerpen, Instituut Born Bunge, Antwerpen, Belgium; Alicia Martinez-Piñeiro, Neuromuscular Unit, Neurology Department, Hospital Germas Trias i Pujol, Spain; Ana Töpf, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Anders Oldfors, Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg Sweden; Anna Kaminska, Department of Neurology Medical University of Warsaw, European Reference Network EURO-N, Varsovia, Poland; Anna Kostera-Pruszczyk, Department of Neurology, Medical University of Warsaw, European Reference Network ERN-NMD, Warsaw, Poland; Anna Mayhew, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Anna Rydelius, Department of Clinical Sciences, Division of Neurology, Lund University, Lund Sweden; Anthony Behin, Unité clinique de pathologie neuromusculaire, Institut de Myologie Hôpital Pitié-Salpêtrière, Paris, France; Antonio Toscano, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Aurelio Hernández Laín, Centro de Referencia Nacional para Enfermedades Neuromusculares Raras CIBERER, Madrid, Spain and Hospital Universitario 12 de octubre, Madrid, España; Beatrice Lannes, Department of Pathology, University Hospital of Strasbourg, France; Beatriz Velez, Neurology Department, Neuromuscular Disorders Unit, Hospital Universitario Virgen del Rocío. Instituto de Biomedicina de Sevilla and Center for Biomedical Network Research on Neurodegenerative Disorders (CIBERNED), Instituto de Salud Carlos III, Madrid Spain; Benedikt Schoser, Friedrich-Baur-Institute, Department of Neurology, LMU Clinics, Munich, Germany; Biruta Kierdaszuk, Department of Neurology, Medical University of Warsaw, European Reference Network EURO-N, Varsovia, Poland; Bjarne Udd, Tampere Neuromuscular Center, Tampere University Hospital, Finland and Folkhalsan Genetic Institute, Helsinki University, Finland; Boel De Paepe, Neurology Department and Neuromuscular Reference Centre, Gent Blegium part of the ERN-NMD; Bruno Eymard, APHP Centre de référence des maladies neuromusculaires Institut de Myologie, Sorbonne Université APHP Hôpital Pitié-Salpêtrière, Paris, France; Carla Marco Cazcarra, Neurology Department, Bellvitge University Hospital, Bellvitge, Spain; Carmelo Rodolico, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; Carmen Paradas, Neurology Department, Neuromuscular Disorders Unit, Hospital Universitario Virgen del Rocío; Instituto de Biomedicina de Sevilla and Center for Biomedical Network Research on Neurodegenerative Disorders (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Carola Hedberg-Oldfors, Department of Laboratory Medicine, Institute of Biomedicine University of Gothenburg, Gothenburg, Sweden; Channa Hewamadduma, Sheffield Institute for translational neurosciences (SITRAN), Neuroscience Institute, University of Sheffield, Sheffield, UK; Cheryl Longman, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Chiara Marini Bettollo, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Chiseko Ikenaga, Johns Hopkins University School of Medicine, Baltimore, USA; Christopher Nance, Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, Iowa, USA; Colin Quinn, Neuromuscular Division, Neurology Department, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Conrad Weihl, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA; Constantinos Papadopoulos, First Department of Neurology, Medical School, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece; Corinne Metay, Sorbonne Université - APHP Centre de Génétique Moléculaire et Chromosomique UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire GH Pitié-Salpêtrière, Paris, France; Cristina Domínguez-González, Neurology Service, Hospital Universitario 12 de Octubre, Madrid, Spain and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain ; David Hilton-Jones, Department of Neurology, John Radcliffe Hospital, Oxford, UK; Edmar Zanotelli, Department of Neurology, School of Medicine, Universidade de São Paulo (FMUSP), São Paulo, Brazil; Edoardo Malfatti, APHP, Neuromuscular Reference Center Nord-Est-Ile-de-France, Henri Mondor Hospital, Université Paris Est, U955, INSERM, Créteil, IMRB, France.; Elena Pegoraro, Department of Neurosciences, University of Padova, Padova, Italy; Elizabeth A. Harrington, Department of Neurology, The Eleanor and Lou Gehrig ALS Center, Columbia University Medical Center, USA; Ellen Eline, Johns Hopkins University School of Medicine, Baltimore, USA; Ellen Gelpi, Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria; Eloy Rivas, Neuropathology Department, University Hospital Virgen del Rocío, Sevilla, Spain and Center for Biomedical Network Research on Neurodegenerative Disorders (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Endre Pál, Department of Neurology, University of Pécs, Hungary; Francesc Miralles, Unitat de Patologia Neuromuscular i Gabinet d'electrodiagnòstic, Servei de Neurologia, Hospital Universitari Son Espases, Palma de Mallorca, Spain; George K Papadimas, First Department of Neurology, Medical School, Eginition Hospital and National and Kapodistrian University of Athens, Athens, Greece; Gergious Manousakis, Department of Neurology, University of Minnesota Hospital, Minneapolis, Minnesota, USA; Gianni Sorarù, Department of Neurosciences, University of Padova, Padova, Italy; Giorgio Tasca, Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Giulia Bisogni, Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Giuseppe Lucente, Neuromuscular Unit, Neurology Department, Hospital Germas Trias i Pujol, Spain; Guillaume Bassez, APHP Centre de référence des maladies neuromusculaires Institut de Myologie, Sorbonne Université, APHP Hôpital Pitié-Salpêtrière, Paris, France; Hakan Cetin, Department of Neurology, Medical University of Vienna, Vienna, Austria; Hani Kushlaf, Department of Neurology & Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA; Ichizo Nishino, Department of Neuromuscular Research National Institute of Neuroscience National Center of Neurology and Psychiatry (NCNP), Japan; Jan L De Bleecker, Department of Neurology and Neuromuscular Reference Center, Ghent University Hospital, Ghent, Belgium, part of the ERN-NMD; Jean François, Deux APHP Centre de référence des maladies neuromusculaires, Institut de Myologie, Sorbonne Université, APHP Hôpital Pitié-Salpêtrière, Paris, France; Jean-Baptiste Chanson, Centre de Reference des Maldies Neuromusculaires Nord-Est-Ile de France, Department of Neurology, University Hospital of Strasbourg, France; Jie Lin, Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China and National Center for Neurological Disorders, Shanghai, China ; Jill Skeoch, Southern General Hospital, Glasgow, UK; Jin-Hong Shin, Laboratory of Molecular Neurology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea; Jodi Warman, Department of Medicine, Ottawa Neuromuscular Centre, Ottawa Hospital, Canada; Johanna Palmio, Tampere Neuromuscular Center, Tampere University Hospital and Tampere University, Finland; Jonathan Baets, Neuromuscular Reference Center, Neurology Department, University Hospital of Antwerp, Belgium; Jordi Díaz-Manera, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK and Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Jorge A Bevilacqua, Unidad Neuromuscular, Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile y Departamento de Neurología y Neurocirugía Clínica, Clínica Dávila, Santiago Chile, Chile; Jorge Alonso Pérez, Unidad de Enfermedades Neuromusculares, Servicio de Neurología, Hospital de la Santa Creu i Sant Pau de Barcelona, España; Jorge Díaz, Centro de Imagenología, Hospital Clínico Universidad de Chile, Chile; Jorge García-García, Neurology department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain; Juan J Vilchez, Neuromuscular Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Judith Hudson, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Kate Taylor, Southern General Hospital, Glasgow, UK; Kinga Hadzsiev, Department of Pathology Neuropathology, Unit University of Pécs, Hungary; Kristl G Claeys, Department of Neurology, University Hospitals Leuven, Leuven, Belgium and KU Leuven Laboratory for Muscle Diseases and Neuropathies, Leuven, Belgium; Lindsay N Alfano, Center for Gene Therapy the Abigail Wexner Research Institute at Nationwide Children’s Hospital Columbus Ohio and Department of Pediatrics, The Ohio State University College of Medicine Columbus Ohio, USA; Luca Bello, Department of Neurosciences, University of Padova, Padova, Italy; Maria Elena Farrugia, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Marianela Schiava, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Marianne de Visser, Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands; Mario Campero, Unidad Neuromuscular, Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Santiago Chile, Chile; Mario Sabatelli, Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Marion Masingue, APHP Centre de référence des maladies neuromusculaires Institut de Myologie, Sorbonne Université APHP Hôpital Pitié-Salpêtrière, Paris, France; Marta Caballero-Ávila, Unidad de Enfermedades Neuromusculares Servicio de Neurología Hospital de la Santa Creu i Sant Pau de Barcelona, España; Matthew B Harms, NewYork Presbyterian Columbia University Irving Medical Centre, New York, New York, USA; Matthias Vorgerd, Heimer Institut for Muscle Research Klinikum Bergmannsheil Ruhr University Bochum, Germany; Mauro Monforte, Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Meredith James, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Michela Guglieri, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Michio Inoue, Department of Neuromuscular Research, National Institute of Neuroscience National Center of Neurology and Psychiatry (NCNP), Japan; Mónica Povedano, Neurology Department, Bellvitge University Hospital, Bellvitge, Spain; Monika Hofer, Department of Neuropathology, Oxford University Hospitals, NHS Foundation Trust, Oxford, UK; Montse Olivé, Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain; Natalia Garcia-Angarita, Friedrich-Baur-Institute, Department of neurology LMU Clinics, Munich, Germany; Nicholas Earle, Departamento de Neurología y Neurocirugía, Clínica Dávila y Clínica Santa María, Santiago Chile, Chile; Noemi Vidal Sarró, Bellvitge University Hospital, Bellvitge, Spain; Nuria Muelas, Neuromuscular Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain; Pascal Lafôret, Neurology department, Raymond-Poincaré hospital, APHP, UVSQ, Paris-Saclay University, Paris, France; Pascale Rihard, Sorbonne Université - APHP Centre de Génétique Moléculaire et Chromosomique UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire GH Pitié-Salpêtrière, Paris, France; Paulo Victor Sgobbi Souza, Disciplina de Neurologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brasil; Peter de Jonghe, Neuromuscular Reference Center, Neurology Department, University Hospital of Antwerp, Belgium; Phillipa J. Lamont, Department of Neurology, Royal Perth Hospital, Western Australia, Australia; Pietro Riguzzi, Department of Neurosciences, University of Padova, Padova, Italy; Pilar Camaño, Biodonostia Neurosciences, Area Group of Neuromuscular Diseases, Biodonostia-Osakidetza Basque Health Service, Molecular Diagnosis Platform, San Sebastián, Spain; Raúl Domínguez Rubio, Neurology Department, Bellvitge University Hospital, Bellvitge, Spain; Robert Carlier, Hôpital Raymond-Poincaré – APHP-Hôpitaux universitaires Paris Ile-de-France Ouest – Garches, France; Robert Muni-Lofra, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK; Roberto Fernández-Torrón, Neurology Department, Biodonostia Health Research Institute, Neuromuscular Area, Hospital Donostia, Basque Health Service, Doctor Begiristain, Donostia-San Sebastian, Spain; Rocío Nur Villar-Quiles, APHP Centre de référence des maladies neuromusculaires Institut de Myologie Sorbonne Université APHP Hôpital Pitié-Salpêtrière, Paris, France; Rodrigo Alvarez, Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain; Rudi Kley, Department of Neurology and Clinical Neurophysiology, St Marien-Hospital Borken, Borken, Germany; Sabine Krause, Friedrich-Baur-Institute, Department of Neurology, LMU Clinics, Munich, Germany; Sarah Leonard-Louis, APHP Centre de référence des maladies neuromusculaires Institut de Myologie Sorbonne Université APHP Hôpital Pitié-Salpêtrière, Paris, France; Sarah Souvannanorath, Centre de référence des maladies neuromusculaires hôpital Henri-Mondor Assistance publique-Hôpitaux de Pars Créteil, France; Sigrid Klotz, Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria; Simone Thiele, Friedrich-Baur-Institute, Department of Neurology, LMU Clinics, Munich, Germany; Sofia Xirou, First Department of Neurology, Medical School, Eginition Hospital and National and Kapodistrian University of Athens, Athens, Greece; Sruthi S Nair, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India; Stefen Brady, Department of Neurology, John Radcliffe Hospital, Oxford, UK; Stojan Peric, Neurology Clinic, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Stuart Ralston, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital Edinburgh, UK; Sushan Luo, Department of Neurology, Huashan Hospital, Fudan University, Shanghai China and National Center for Neurological Disorders, Shanghai, China; Tanya Stojkovic, APHP Centre de référence des maladies neuromusculaires Institut de Myologie, Sorbonne Université, APHP Hôpital Pitié-Salpêtrière, Paris, France; Teresinha Evangelista, APHP Centre de référence des maladies neuromusculaires Institut de Myologie Sorbonne Université APHP Hôpital Pitié-Salpêtrière, Paris, France; Thomas E Lloyd, Johns Hopkins University School of Medicine, Baltimore, USA; Tiffany Grider, Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa, USA ; Timothy Williams, Newcastle Motor Neurone Disease Care Centre, Royal Victoria Infirmary, Newcastle, UK; Umesh Badrising, Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands; Velina Nedkova-Hristova, Neurology Department, Bellvitge University Hospital, Bellvitge, Spain; Vidosava Rakocevic-Stojanovic, Neurology Clinic, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Serbia; Virginia Kimonis, Department of Pediatrics, Division of Genetics and Genomic Medicine, University of California-Irvine Medical Center; Children’s Hospital of Orange County Orange, USA ; Volker Straub, John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle, UK ; Wenhua Zhu, Department of Neurology, Huashan Hospital Fudan University, Shanghai, China and National Center for Neurological Disorders, Shanghai, China; Willem de Ridder, Neuromuscular Reference Center, Neurology Department, University Hospital of Antwerp, Belgium; William Kelly, Johns Hopkins University School of Medicine, Baltimore, USA; Yoshihiko Saito, Department of Neuromuscular Research National Institute of Neuroscience National Center of Neurology and Psychiatry (NCNP), Japan ; Young-Eun Park, Laboratory of Molecular Neurology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea; Yukako Nishimori, Department of Neuromuscular Research National Institute of Neuroscience National Center of Neurology and Psychiatry (NCNP), Japan; Zarife Sahenk, Center for Gene Therapy the Abigail Research Institute at Nationwide Children’s Hospital, Columbus, Ohio and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.

      • Contributors MS: Conceptualised the study, Acquisition of data, analysed the data, drafted the manuscript for intellectual content. CI: Conceptualised the study, Acquisition of data, drafted the manuscript for intellectual content. RNV-Q: Conceptualised the study, Acquisition of data, drafted the manuscript for intellectual content. MC-Á: Conceptualised the study, Acquisition of data, drafted the manuscript for intellectual content. TS: Conceptualised the study, Acquisition of data, drafted the manuscript for intellectual content. CCW: Conceptualised the study, Acquisition of data, drafted the manuscript for intellectual content. JD-M: Conceptualised the study, Acquisition of data, analysed the data, drafted the manuscript for intellectual content. AL-dM: Acquisition of data and revision of the manuscript for intellectual content. AR-F: Acquisition of data and revision of the manuscript for intellectual content. AN-P: Acquisition of data and revision of the manuscript for intellectual content. AA-J: Acquisition of data and revision of the manuscript for intellectual content. AM-P: Acquisition of data and revision of the manuscript for intellectual content. AT: Acquisition of data and revision of the manuscript for intellectual content. AO: Acquisition of data and revision of the manuscript for intellectual content. AK: Acquisition of data and revision of the manuscript for intellectual content. AK-P: Acquisition of data and revision of the manuscript for intellectual content. AM: Acquisition of data and revision of the manuscript for intellectual content. AR: Acquisition of data and revision of the manuscript for intellectual content. AB: Acquisition of data and revision of the manuscript for intellectual content. AT: Acquisition of data and revision of the manuscript for intellectual content. AHL: Acquisition of data and revision of the manuscript for intellectual content. BL: Acquisition of data and revision of the manuscript for intellectual content. BV: Acquisition of data and revision of the manuscript for intellectual content. BS: Acquisition of data and revision of the manuscript for intellectual content. BK: Acquisition of data and revision of the manuscript for intellectual content. BU: Acquisition of data and revision of the manuscript for intellectual content. BDP: Acquisition of data and revision of the manuscript for intellectual content. BE: Acquisition of data and revision of the manuscript for intellectual content. CMC: Acquisition of data and revision of the manuscript for intellectual content CR: Acquisition of data and revision of the manuscript for intellectual content. CP: Acquisition of data and revision of the manuscript for intellectual content. CH-O: Acquisition of data and revision of the manuscript for intellectual content. CH: Acquisition of data and revision of the manuscript for intellectual content. CL: Acquisition of data and revision of the manuscript for intellectual content. CMB: Acquisition of data and revision of the manuscript for intellectual content. CN: Acquisition of data and revision of the manuscript for intellectual content. CQ: Acquisition of data and revision of the manuscript for intellectual content. CP: Acquisition of data and revision of the manuscript for intellectual content. CM: Acquisition of data and revision of the manuscript for intellectual content. CD-G: Acquisition of data and revision of the manuscript for intellectual content. DH-J: Acquisition of data and revision of the manuscript for intellectual content. EZ: Acquisition of data and revision of the manuscript for intellectual content. EM: Acquisition of data and revision of the manuscript for intellectual content. EP: Acquisition of data and revision of the manuscript for intellectual content. EAH: Acquisition of data and revision of the manuscript for intellectual content. EE: Acquisition of data and revision of the manuscript for intellectual content. EG: Acquisition of data and revision of the manuscript for intellectual content. ER: Acquisition of data and revision of the manuscript for intellectual content. EP: Acquisition of data and revision of the manuscript for intellectual content. FMM: Acquisition of data and revision of the manuscript for intellectual content. GKP: Acquisition of data and revision of the manuscript for intellectual content. GM: Acquisition of data and revision of the manuscript for intellectual content. GS: Acquisition of data and revision of the manuscript for intellectual content. GT: Acquisition of data and revision of the manuscript for intellectual content. GB: Acquisition of data and revision of the manuscript for intellectual content. GL: Acquisition of data and revision of the manuscript for intellectual content. GB: Acquisition of data and revision of the manuscript for intellectual content. HC: Acquisition of data and revision of the manuscript for intellectual content. HK: Acquisition of data and revision of the manuscript for intellectual content. IN: Acquisition of data and revision of the manuscript for intellectual content. JDB: Acquisition of data and revision of the manuscript for intellectual content. JF: Acquisition of data and revision of the manuscript for intellectual content. JBC: Acquisition of data and revision of the manuscript for intellectual content. JL: Acquisition of data and revision of the manuscript for intellectual content. JS: Acquisition of data and revision of the manuscript for intellectual content. J-HS: Acquisition of data and revision of the manuscript for intellectual content. JH-S: Acquisition of data and revision of the manuscript for intellectual content. JW: Acquisition of data and revision of the manuscript for intellectual content. JP: Acquisition of data and revision of the manuscript for intellectual content. JB: Acquisition of data and revision of the manuscript for intellectual content. JAB: Acquisition of data and revision of the manuscript for intellectual content. JAP: Acquisition of data and revision of the manuscript for intellectual content. JD: Acquisition of data and revision of the manuscript for intellectual content. JG-G: Acquisition of data and revision of the manuscript for intellectual content. JJV: Acquisition of data and revision of the manuscript for intellectual content. JH: Acquisition of data and revision of the manuscript for intellectual content. KT: Acquisition of data and revision of the manuscript for intellectual content. KH: Acquisition of data and revision of the manuscript for intellectual content. KGC: Acquisition of data and revision of the manuscript for intellectual content. LNA: Acquisition of data and revision of the manuscript for intellectual content. LB: Acquisition of data and revision of the manuscript for intellectual content. MEF: Acquisition of data and revision of the manuscript for intellectual content. MdV: Acquisition of data and revision of the manuscript for intellectual content. MC: Acquisition of data and revision of the manuscript for intellectual content. MS: Acquisition of data and revision of the manuscript for intellectual content. MM: Acquisition of data and revision of the manuscript for intellectual content. MBH: Acquisition of data and revision of the manuscript for intellectual content. MV: Acquisition of data and revision of the manuscript for intellectual content. MM: Acquisition of data and revision of the manuscript for intellectual content. MJ: Acquisition of data and revision of the manuscript for intellectual content. MG: Acquisition of data and revision of the manuscript for intellectual content. MI: Acquisition of data and revision of the manuscript for intellectual content. MP: Acquisition of data and revision of the manuscript for intellectual content. MH: Acquisition of data and revision of the manuscript for intellectual content. MO: Acquisition of data and revision of the manuscript for intellectual content. NG-A: Acquisition of data and revision of the manuscript for intellectual content. NE: Acquisition of data and revision of the manuscript for intellectual content. NVS: Acquisition of data and revision of the manuscript for intellectual content. NM: Acquisition of data and revision of the manuscript for intellectual content. PL: Acquisition of data and revision of the manuscript for intellectual content. PR: Acquisition of data and revision of the manuscript for intellectual content. PVSS: Acquisition of data and revision of the manuscript for intellectual content PdJ: Acquisition of data and revision of the manuscript for intellectual content. PJL: Acquisition of data and revision of the manuscript for intellectual content. PR: Acquisition of data and revision of the manuscript for intellectual content. PC: Acquisition of data and revision of the manuscript for intellectual content. RDR: Acquisition of data and revision of the manuscript for intellectual content. RC: Acquisition of data and revision of the manuscript for intellectual content. RML: Acquisition of data and revision of the manuscript for intellectual content. RFT: Acquisition of data and revision of the manuscript for intellectual content. RA: Acquisition of data and revision of the manuscript for intellectual content. RK: Acquisition of data and revision of the manuscript for intellectual content. SK: Acquisition of data and revision of the manuscript for intellectual content. SLL: Acquisition of data and revision of the manuscript for intellectual content. SK: Acquisition of data and revision of the manuscript for intellectual content. ST: Acquisition of data and revision of the manuscript for intellectual content. SX: Acquisition of data and revision of the manuscript for intellectual content. SS: Acquisition of data and revision of the manuscript for intellectual content. SSN: Acquisition of data and revision of the manuscript for intellectual content. SB: Acquisition of data and revision of the manuscript for intellectual content. SP: Acquisition of data and revision of the manuscript for intellectual content. SR: Acquisition of data and revision of the manuscript for intellectual content. SL: Acquisition of data and revision of the manuscript for intellectual content. TE: Acquisition of data and revision of the manuscript for intellectual content. TL: Acquisition of data and revision of the manuscript for intellectual content. TG: Acquisition of data and revision of the manuscript for intellectual content. TW: Acquisition of data and revision of the manuscript for intellectual content. UB: Acquisition of data and revision of the manuscript for intellectual content. VN-H: Acquisition of data and revision of the manuscript for intellectual content. VRS: Acquisition of data and revision of the manuscript for intellectual content. VK: Acquisition of data and revision of the manuscript for intellectual content. VS: Acquisition of data and revision of the manuscript for intellectual content. WZ: Acquisition of data and revision of the manuscript for intellectual content. WdR: Acquisition of data and revision of the manuscript for intellectual content. WK: Acquisition of data and revision of the manuscript for intellectual content. YS: Acquisition of data and revision of the manuscript for intellectual content. YEP: Acquisition of data and revision of the manuscript for intellectual content. YN: Acquisition of data and revision of the manuscript for intellectual content. ZS: Acquisition of data and revision of the manuscript for intellectual content. Guarantor authors: MS and JD-M.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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