Disease spectrum and long-term prognosis of patients with <i>BAG3</i> -associated neuromuscular diseases in Europe

De novo or autosomal dominant BAG3 gene variants cause a wide range of skeletal and cardiac muscle diseases encompassing Charcot-Marie-Tooth disease, myofibrillar myopathy, cardiomyopathy or a combination of them. Given the severity and rarity of BAG3-neuromuscular diseases (NMDs), series of patients are lacking. Our aim was to characterize the clinical and genetic spectrum, in addition to the natural history of BAG3-NMDs in Europe. In this multicentre retrospective study, we collected clinical, ancillary and genetic data of patients with NMD and BAG3 variants, identified from European paediatric and adult neuromuscular reference centres from May to December 2023 following a call circulated through the European Reference Network EURO-NMD and other partners. Responses were received from 35 centres in 17 countries. Twenty-six patients (65.4% males, 34.6% females) with BAG3-NMD from 18 different families were included in the study. The c.626C>T p.(Pro209Leu) variant, carried by 16 patients, was the only recurrent variant and was associated with a homogeneous and severe phenotype, with predominantly lower limb motor weakness (n = 13, 81.25%) or heart failure (n = 3, 18.75%) as the presenting feature and with a mean age at symptom onset of 7.8 ± 3.4 years. Where available (n = 13), electroneuromyography showed a polyneuropathy with demyelinating features and a frequently associated myopathy. Eleven (68.8%) patients had restrictive cardiomyopathy on initial assessment. Orthopaedic manifestations were common, with contractures (n = 15, 93.8%), foot deformities (n = 11, 84.6%) and scoliosis and/or rigid spine (n = 12, 80%). At last follow-up (age 21.5 ± 8.6 years) of the patients carrying the p.(Pro209Leu) variant, 10 (62.5%) had lost ambulation, 14 (93.3%) had respiratory insufficiency (11 requiring ventilation) and 12 (75%) had a restrictive cardiomyopathy, leading to heart failure and heart transplantation in five and four patients, respectively. Eight (50%) patients died prematurely at a mean age of 22.5 ± 9.6 years, most frequently from sudden death (n = 5). The other 10 patients carried three other BAG3 variants and showed a milder disease course, with all patients remaining ambulatory, without cardiorespiratory manifestations at last follow-up. The p.(Arg309*) nonsense variant, known to cause isolated dilated cardiomyopathy, and the p.(Val505Glyfs*6) frameshift variant, resulting in a premature stop codon, caused distal hereditary motor neuropathy. This is the largest study of patients with BAG3-NMD, delineating the frequency, specific presentation and natural history in patients with the recurrent BAG3 p.(Pro209Leu) missense variant, crucial for informing patient management in the context of a rapidly progressive disease. All other BAG3 variants were rare and caused milder clinical presentations.

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Journal
Brain
Published
2025-06-07
DOI
https://doi.org/10.1093/brain/awaf223
Citations
1
Primary Topic
Cardiomyopathy and Myosin Studies
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article
Field-Weighted Citation Impact
1.39
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article

Disease spectrum and long-term prognosis of patients with BAG3 -associated neuromuscular diseases in Europe

John Vissing, Maggie Christine Walter, Maike Franziska Dohrn, Carlos Pablo de Fuenmayor‐Fernández de la Hoz et al.
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Cardiomyopathy and Myosin Studies
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article

Disease spectrum and long-term prognosis of patients with BAG3 -associated neuromuscular diseases in Europe

John Vissing, Maggie Christine Walter, Maike Franziska Dohrn, Carlos Pablo de Fuenmayor‐Fernández de la Hoz, Montse Olivé, Volker Straub, Karim Wahbi, Anna Potulska‐Chromik, Germán Morís, Heinz Jungbluth, Corrado Italo Angelini, Kristl G. Claeys, Ulrike Schara‐Schmidt, Cristina Domínguez‐González, Corinne Métay, Chiara Marini‐Bettolo, Enrico Bertini, Simone Thiele, Frédérique Audic, Eduard Gallardo, Pascale Richard, Anna Kostera‐Pruszczyk, Guy Brochier, M Dembélé, Cyril Gitiaux, Frédéric Fer, Gorka Fernández‐Eulate, Diala Khraiche, Shahram Attarian, Jean Baptiste Davion, Arnaud Isapof, Teresinha Evangelista, Tanya Stojkovic
article en
1 citations

Abstract

De novo or autosomal dominant BAG3 gene variants cause a wide range of skeletal and cardiac muscle diseases encompassing Charcot-Marie-Tooth disease, myofibrillar myopathy, cardiomyopathy or a combination of them. Given the severity and rarity of BAG3-neuromuscular diseases (NMDs), series of patients are lacking. Our aim was to characterize the clinical and genetic spectrum, in addition to the natural history of BAG3-NMDs in Europe. In this multicentre retrospective study, we collected clinical, ancillary and genetic data of patients with NMD and BAG3 variants, identified from European paediatric and adult neuromuscular reference centres from May to December 2023 following a call circulated through the European Reference Network EURO-NMD and other partners. Responses were received from 35 centres in 17 countries. Twenty-six patients (65.4% males, 34.6% females) with BAG3-NMD from 18 different families were included in the study. The c.626C>T p.(Pro209Leu) variant, carried by 16 patients, was the only recurrent variant and was associated with a homogeneous and severe phenotype, with predominantly lower limb motor weakness (n = 13, 81.25%) or heart failure (n = 3, 18.75%) as the presenting feature and with a mean age at symptom onset of 7.8 ± 3.4 years. Where available (n = 13), electroneuromyography showed a polyneuropathy with demyelinating features and a frequently associated myopathy. Eleven (68.8%) patients had restrictive cardiomyopathy on initial assessment. Orthopaedic manifestations were common, with contractures (n = 15, 93.8%), foot deformities (n = 11, 84.6%) and scoliosis and/or rigid spine (n = 12, 80%). At last follow-up (age 21.5 ± 8.6 years) of the patients carrying the p.(Pro209Leu) variant, 10 (62.5%) had lost ambulation, 14 (93.3%) had respiratory insufficiency (11 requiring ventilation) and 12 (75%) had a restrictive cardiomyopathy, leading to heart failure and heart transplantation in five and four patients, respectively. Eight (50%) patients died prematurely at a mean age of 22.5 ± 9.6 years, most frequently from sudden death (n = 5). The other 10 patients carried three other BAG3 variants and showed a milder disease course, with all patients remaining ambulatory, without cardiorespiratory manifestations at last follow-up. The p.(Arg309*) nonsense variant, known to cause isolated dilated cardiomyopathy, and the p.(Val505Glyfs*6) frameshift variant, resulting in a premature stop codon, caused distal hereditary motor neuropathy. This is the largest study of patients with BAG3-NMD, delineating the frequency, specific presentation and natural history in patients with the recurrent BAG3 p.(Pro209Leu) missense variant, crucial for informing patient management in the context of a rapidly progressive disease. All other BAG3 variants were rare and caused milder clinical presentations.

BrainVol. 148(12)
Hôpital Necker-Enfants Malades (FR), Allen Institute for Brain Science (US), St Thomas' Hospital (GB), University of Padua (IT), Inserm (FR), Morpho (United States) (US), King's College London (GB), Guy's and St Thomas' NHS Foundation Trust (GB), Université Paris Cité (FR), Medical University of Warsaw (PL), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Hospital de Sant Pau (ES), Copenhagen University Hospital (DK), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), Institut Necker Enfants Malades (FR), Hôpital Armand-Trousseau (FR), Hôpital Cochin (FR), Assistance Publique – Hôpitaux de Paris (FR), Association Francaise contre les Myopathies (FR), Centre for Biomedical Network Research on Rare Diseases (ES), Laboratoire National de Référence (MA), Institut de Myologie (FR), Universitätsklinikum Aachen (DE), Pitié-Salpêtrière Hospital (FR), St. Thomas Hospital (CA), Bambino Gesù Children's Hospital (IT), Friedrich Baur Stiftung (DE), Hospital Universitario Central de Asturias (ES), Institut de Neurosciences de la Timone (FR), Unité de recherche sur les maladies cardiovasculaires et métaboliques (FR), VIB-KU Leuven Center for Brain & Disease Research (BE), Hôpital de la Timone (FR), Institut des Maladies Génétiques Imagine (FR), Centre de Recherche en Myologie, Université Lille Nord de France (FR), University of Duisburg-Essen (DE), University of Newcastle Australia (AU), Ludwig-Maximilians-Universität München (DE), Newcastle University (GB), RWTH Aachen University (DE), KU Leuven (BE)
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Cardiomyopathy and Myosin Studies
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