Deep phenotyping of an international series of patients with late-onset dysferlinopathy
Gorka Fernández-Eulate
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (equal), Resources (equal), Software (lead), Writing - original draft (lead)
Search for more papers by this authorGiorgia Querin
Plateforme I-Motion Adultes, Service de Neuromyologie, Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Formal analysis (equal), Methodology (supporting), Project administration (supporting), Software (equal), Writing - review & editing (supporting)
Search for more papers by this authorUrsula Moore
John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Contribution: Data curation (equal), Formal analysis (supporting), Methodology (supporting), Resources (equal), Software (supporting), Writing - review & editing (supporting)
Search for more papers by this authorAnthony Behin
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorMarion Masingue
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting), Writing - review & editing (supporting)
Search for more papers by this authorGuillaume Bassez
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorSarah Leonard-Louis
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorPascal Laforêt
Nord-Est/Ile-de-France Neuromuscular Reference Center, FHU PHENIX, Neurology Department, Raymond-Poincaré Hospital, Versailles Saint-Quentin-en-Yvelines - Paris Saclay University, Garches, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorThierry Maisonobe
Department of Clinical Neurophysiology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorPhilippe-Edouard Merle
Department of Clinical Neurophysiology, Amiens University Hospital, Amiens, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorMarco Spinazzi
Neuromuscular Reference Center, Angers University Hospital, Angers, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorGuilhem Solé
Referral Center for Neuromuscular Diseases ‘AOC’, Nerve-Muscle Unit, Bordeaux University Hospitals (Pellegrin Hospital), Bordeaux, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorThierry Kuntzer
Nerve-Muscle Unit, Department of Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorAnne-Laure Bedat-Millet
Neuromuscular Reference Center, Rouen University Hospital, Rouen, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorEmmanuelle Salort-Campana
PACA Réunion Rhone Alpes Neuromuscular Reference Center, APHM, La Timone University Hospital, Marseille, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorShahram Attarian
PACA Réunion Rhone Alpes Neuromuscular Reference Center, APHM, La Timone University Hospital, Marseille, France
Contribution: Resources (equal)
Search for more papers by this authorYann Péréon
Reference Center for Neuromuscular Diseases Atlantique-Occitanie-Caraïbes, Nantes University Hospital, Nantes, France
Contribution: Conceptualization (supporting), Resources (supporting)
Search for more papers by this authorLeonard Feasson
Neuromuscular Reference Center, Unit of Myology, Inter-University Laboratory of Human Movement Biology, Saint-Etienne University Hospital, Saint-Étienne, France
Contribution: Data curation (equal), Resources (supporting)
Search for more papers by this authorJulie Graveleau
Neuromuscular Reference Center, Saint-Nazaire Hospital, Saint-Nazaire, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorAleksandra Nadaj-Pakleza
Nord-Est/Ile-de-France Neuromuscular Reference Center, Department of Neurology, Strasbourg University Hospital, Strasbourg, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorFrance Leturcq
Genetics and Molecular Biology Laboratory, Cochin University Hospital, Paris, France
Contribution: Data curation (equal), Investigation (supporting), Resources (equal), Writing - review & editing (supporting)
Search for more papers by this authorSvetlana Gorokhova
Inserm, U1251-MMG, Marseille Medical Genetics, Aix-Marseille University, Marseille, France
Département de Génétique Médicale, Hôpital Timone Enfants, APHM, Marseille, France
Contribution: Formal analysis (supporting), Software (supporting), Writing - review & editing (supporting)
Search for more papers by this authorMartin Krahn
Inserm, U1251-MMG, Marseille Medical Genetics, Aix-Marseille University, Marseille, France
Département de Génétique Médicale, Hôpital Timone Enfants, APHM, Marseille, France
Contribution: Data curation (equal), Investigation (supporting), Resources (equal), Writing - review & editing (supporting)
Search for more papers by this authorBruno Eymard
Nord-Est/Ile-de-France Neuromuscular Reference Center, Neurology Department, Raymond-Poincaré Hospital, Sorbonne University, Garches, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorVolker Straub
John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Contribution: Conceptualization (supporting), Resources (equal)
Search for more papers by this authorJain COS Consortium
Search for more papers by this authorTeresinha Evangelista
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Investigation (equal), Methodology (supporting), Resources (supporting), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Tanya Stojkovic
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Correspondence
Tanya Stojkovic, Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, 47-83 boulevard de l'Hôpital, Paris Cedex 13, France.
Email: [email protected]
Contribution: Conceptualization (lead), Investigation (equal), Methodology (equal), Project administration (equal), Resources (equal), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorGorka Fernández-Eulate
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (equal), Resources (equal), Software (lead), Writing - original draft (lead)
Search for more papers by this authorGiorgia Querin
Plateforme I-Motion Adultes, Service de Neuromyologie, Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Formal analysis (equal), Methodology (supporting), Project administration (supporting), Software (equal), Writing - review & editing (supporting)
Search for more papers by this authorUrsula Moore
John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Contribution: Data curation (equal), Formal analysis (supporting), Methodology (supporting), Resources (equal), Software (supporting), Writing - review & editing (supporting)
Search for more papers by this authorAnthony Behin
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorMarion Masingue
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting), Writing - review & editing (supporting)
Search for more papers by this authorGuillaume Bassez
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorSarah Leonard-Louis
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorPascal Laforêt
Nord-Est/Ile-de-France Neuromuscular Reference Center, FHU PHENIX, Neurology Department, Raymond-Poincaré Hospital, Versailles Saint-Quentin-en-Yvelines - Paris Saclay University, Garches, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorThierry Maisonobe
Department of Clinical Neurophysiology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorPhilippe-Edouard Merle
Department of Clinical Neurophysiology, Amiens University Hospital, Amiens, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorMarco Spinazzi
Neuromuscular Reference Center, Angers University Hospital, Angers, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorGuilhem Solé
Referral Center for Neuromuscular Diseases ‘AOC’, Nerve-Muscle Unit, Bordeaux University Hospitals (Pellegrin Hospital), Bordeaux, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorThierry Kuntzer
Nerve-Muscle Unit, Department of Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorAnne-Laure Bedat-Millet
Neuromuscular Reference Center, Rouen University Hospital, Rouen, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorEmmanuelle Salort-Campana
PACA Réunion Rhone Alpes Neuromuscular Reference Center, APHM, La Timone University Hospital, Marseille, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorShahram Attarian
PACA Réunion Rhone Alpes Neuromuscular Reference Center, APHM, La Timone University Hospital, Marseille, France
Contribution: Resources (equal)
Search for more papers by this authorYann Péréon
Reference Center for Neuromuscular Diseases Atlantique-Occitanie-Caraïbes, Nantes University Hospital, Nantes, France
Contribution: Conceptualization (supporting), Resources (supporting)
Search for more papers by this authorLeonard Feasson
Neuromuscular Reference Center, Unit of Myology, Inter-University Laboratory of Human Movement Biology, Saint-Etienne University Hospital, Saint-Étienne, France
Contribution: Data curation (equal), Resources (supporting)
Search for more papers by this authorJulie Graveleau
Neuromuscular Reference Center, Saint-Nazaire Hospital, Saint-Nazaire, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorAleksandra Nadaj-Pakleza
Nord-Est/Ile-de-France Neuromuscular Reference Center, Department of Neurology, Strasbourg University Hospital, Strasbourg, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorFrance Leturcq
Genetics and Molecular Biology Laboratory, Cochin University Hospital, Paris, France
Contribution: Data curation (equal), Investigation (supporting), Resources (equal), Writing - review & editing (supporting)
Search for more papers by this authorSvetlana Gorokhova
Inserm, U1251-MMG, Marseille Medical Genetics, Aix-Marseille University, Marseille, France
Département de Génétique Médicale, Hôpital Timone Enfants, APHM, Marseille, France
Contribution: Formal analysis (supporting), Software (supporting), Writing - review & editing (supporting)
Search for more papers by this authorMartin Krahn
Inserm, U1251-MMG, Marseille Medical Genetics, Aix-Marseille University, Marseille, France
Département de Génétique Médicale, Hôpital Timone Enfants, APHM, Marseille, France
Contribution: Data curation (equal), Investigation (supporting), Resources (equal), Writing - review & editing (supporting)
Search for more papers by this authorBruno Eymard
Nord-Est/Ile-de-France Neuromuscular Reference Center, Neurology Department, Raymond-Poincaré Hospital, Sorbonne University, Garches, France
Contribution: Data curation (supporting), Resources (supporting)
Search for more papers by this authorVolker Straub
John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Contribution: Conceptualization (supporting), Resources (equal)
Search for more papers by this authorJain COS Consortium
Search for more papers by this authorTeresinha Evangelista
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Contribution: Data curation (supporting), Investigation (equal), Methodology (supporting), Resources (supporting), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Tanya Stojkovic
Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France
Correspondence
Tanya Stojkovic, Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, 47-83 boulevard de l'Hôpital, Paris Cedex 13, France.
Email: [email protected]
Contribution: Conceptualization (lead), Investigation (equal), Methodology (equal), Project administration (equal), Resources (equal), Supervision (equal), Writing - review & editing (equal)
Search for more papers by this authorFunding information
The International Clinical Outcome Study for dysferlinopathy (COS study) was funded by the JAIN Foundation.
Abstract
Background
To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients.
Methods
Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30 years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited.
Results
Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range 30–57) years and most patients showed a limb-girdle (n = 26) or distal (n = 10) phenotype. However, compared with EO dysferlinopathy patients (n = 48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p = 0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p = 0.01), and higher NSAD (p = 0.008) and ACTIVLIM scores (p = 0.016). Loss of ambulation in LO patients tended to occur later (23 ± 4.4 years after disease onset vs. 16.3 ± 6.8 years; p = 0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p = 0.021), no differences in dysferlin protein expression were found on Western blot.
Conclusions
Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.
CONFLICT OF INTEREST
All authors declared no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
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| ene14821-sup-0001-TabS1.docxWord document, 27.2 KB | Tab S1 |
| ene14821-sup-0002-TabS2.docxWord document, 27.9 KB | Tab S2 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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