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Lookup NU author(s): Professor Chiara Marini Bettolo, Professor Volker StraubORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. 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.
Author(s): Fernandez-Eulate G, Gitiaux C, Thiele S, Jungbluth H, Potulska-Chromik A, Marini-Bettolo C, Davion JB, Moris G, Gallardo E, Olive M, de Fuenmayor-Fernandez de la Hoz CP, Audic F, Isapof A, Walter MC, Angelini C, Bertini E, Schara-Schmidt U, Claeys KG, Dohrn MF, Dembele M, Fer F, Brochier G, Evangelista T, Kostera-Pruszczyk A, Attarian S, Straub V, Dominguez-Gonzalez C, Vissing J, Richard P, Metay C, Khraiche D, Wahbi K, Stojkovic T
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2025
Volume: 148
Issue: 12
Pages: 4435-4447
Print publication date: 01/12/2025
Online publication date: 10/06/2025
Acceptance date: 17/05/2025
Date deposited: 15/12/2025
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: https://doi.org/10.1093/brain/awaf223
DOI: 10.1093/brain/awaf223
Data Access Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
PubMed id: 40493734
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