International retrospective natural history study of LMNA-related congenital muscular dystrophy
Por:
Ben Yaou R, Yun P, Dabaj I, Norato G, Donkervoort S, Xiong H, Nascimento-Osorio A, Maggi L, Sarkozy A, Monges S, Bertoli M, Komaki H, Mayer M, Mercuri E, Zanoteli E, Castiglioni C, Marini-Bettolo C, D'Amico A, Deconinck N, Desguerre I, Erazo-Torricelli R, Gurgel-Giannetti J, Ishiyama A, Kleinsteuber KS, Lagrue E, Laugel V, Mercier S, Messina S, Politano L, Ryan MM, Sabouraud P, Schara U, Siciliano G, Vercelli L, Voit T, Yoon G, Alvarez R, Muntoni F, Pierson TM, Gómez-Andrés D, Reghan Foley A, Quijano-Roy S, Bönnemann CG and Bonne G
Publicada:
1 ene 2021
Ahead of Print:
11 abr 2021
Resumen:
Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.
Filiaciones:
Ben Yaou R:
Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, F-75013 Paris, France
APHP-Sorbonne Université, Neuromuscular Disorders Reference Center of Nord-Est-Île de France, FILNEMUS, ERN-Euro-NMD, Service de Neuromyologie, Institute de Myologie, G.H. Pitié-Salpêtrière Paris F-75013, France
Yun P:
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Dabaj I:
APHP-Université Paris-Saclay, Neuromuscular Disorders Reference Center of Nord-Est-Île de France, FILNEMUS, ERN-Euro-NMD, Pediatric Neurology and ICU Department, DMU Santé Enfant Adolescent (SEA), Raymond Poincaré University Hospital, Garches France
INSERM U 1245, ED497, School of Medicine, Rouen University, Rouen, France
Norato G:
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Donkervoort S:
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Xiong H:
INSERM U 1245, ED497, School of Medicine, Rouen University, Rouen, France
Nascimento-Osorio A:
Department of Pediatrics, Peking University First Hospital, Beijing, China
Maggi L:
Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, CIBERER - ISC III, Barcelona, Spain
Sarkozy A:
Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Instituto Neurologico Carlo Besta, Milano, Italy
Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital Trust, London, UK
Monges S:
Servicio de Neurología, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina
Bertoli M:
Northern Genetics Service, The Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
Komaki H:
Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
Mayer M:
APHP-Sorbonne Université, Neuromuscular Disorders Reference Center of Nord-Est-Île de France, FILNEMUS, ERN-Euro-NMD, Department of Neuropediatrics, Hôpital Armand Trousseau, Paris, France
Mercuri E:
Paediatric Neurology, Policlinico Gemelli, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Zanoteli E:
Department of Neurology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
Castiglioni C:
Pediatric Neurology Department, Clínica Las Condes, Santiago, Chile
Marini-Bettolo C:
John Walton Muscular Dystrophy Research Centre, Institute of Integrated Laboratory Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
D'Amico A:
Unit of Muscular and Neurodegenerative diseases, Department of Neurological and Psychiatric science,s Bambino Gesù Children's Hospital, Rome, Italy
Deconinck N:
Paediatric Neurology Department and neuromuscular Center, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
Desguerre I:
APHP-Centre - Université de Paris, Neuromuscular Disorders Reference Center of Nord-Est-Île de France, FILNEMUS, ERN-Euro-NMD, Necker-Enfants Malades Hospital, Paris, France
Erazo-Torricelli R:
Neurología Pediátrica, Unidad Neuromuscular, Hospital Luis Calvo Mackenna, Clínica Alemana de Santiago, Santiago, Chile
Gurgel-Giannetti J:
Department of Pediatrics, Pediatric Neurology Service, Medical School, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Ishiyama A:
Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
Kleinsteuber KS:
Neurología Pediátrica Hospital Roberto del Río- Universidad de Chile - Clínica Las Condes Santiago, Chile
Lagrue E:
CHRU de Tours, Université François Rabelais de Tours, INSERM U1253, Tours, France
Laugel V:
Department of neuropediatrics, CHU Strasbourg- Hautepierre, Strasbourg, France
Mercier S:
Service de Génétique médicale, INSERM, CNRS, UNIV Nantes, CHU Nantes, l'institut du Thorax, Nantes, France
Messina S:
Unit of Neurology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
Politano L:
Cardiomiology and Medical Genetics, Department of Experimental Medicine, University of Campania, Naples, Italy
Ryan MM:
Children's Neurosciences Centre, Royal Children's Hospital, Victoria, Australia
Sabouraud P:
Service de Pédiatrie A, Neurologie pédiatrique, CHU de Reims, American Memorial Hospital, Reims, France
Schara U:
Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Children's Hospital 1, University of Duisburg-Essen, Essen, Germany
Siciliano G:
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Vercelli L:
Department of Neuroscience, Center for Neuromuscular Diseases, University of Turin, Turin, Italy
Voit T:
Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Instituto Neurologico Carlo Besta, Milano, Italy
National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
Yoon G:
Divisions of Neurology and Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Alvarez R:
Congenital Muscle Disease International Registry (CMDIR), Cure CMD, Lakewood, CA, USA
Muntoni F:
Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Instituto Neurologico Carlo Besta, Milano, Italy
National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
Pierson TM:
Departments of Pediatrics and Neurology and the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Gómez-Andrés D:
Pediatric Neurology (ERN-RND - EURO-NMD), Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
Reghan Foley A:
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Quijano-Roy S:
APHP-Université Paris-Saclay, Neuromuscular Disorders Reference Center of Nord-Est-Île de France, FILNEMUS, ERN-Euro-NMD, Pediatric Neurology and ICU Department, DMU Santé Enfant Adolescent (SEA), Raymond Poincaré University Hospital, Garches France
INSERM U 1179, University of Versailles Saint-Quentin-en-Yvelines (UVSQ), France
Bönnemann CG:
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Bonne G:
Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, F-75013 Paris, France
APHP-Sorbonne Université, Neuromuscular Disorders Reference Center of Nord-Est-Île de France, FILNEMUS France, ERN-Euro-NMD, Paris, France
Green Submitted, gold
|