Clinical Spectrum and Outcomes of BAG3-Related Neuromuscular Disorders in Europe
Overview
This multicentre European study characterized 26 patients with BAG3-related neuromuscular disorders, highlighting a severe phenotype associated with the recurrent p.(Pro209Leu) variant. Patients with this variant exhibited early onset motor weakness, cardiomyopathy, respiratory insufficiency, and high mortality, whereas other BAG3 variants showed milder disease.
Background
BAG3 gene variants cause a spectrum of neuromuscular and cardiac diseases including Charcot–Marie–Tooth disease, myofibrillar myopathy, and cardiomyopathy. BAG3 is critical for muscle structural integrity and protein quality control via chaperone-assisted selective autophagy. The p.(Pro209Leu) variant has been linked to a severe, rapidly progressive neuromuscular phenotype with multisystem involvement. Understanding the clinical spectrum and natural history is essential for patient management and future therapeutic development.
Data Highlights
Feature
Patients with p.(Pro209Leu) Variant (n=16)
Mean age at symptom onset
7.8 ± 3.4 years
Lower limb motor weakness at presentation
13 (81.25%)
Heart failure at presentation
3 (18.75%)
Restrictive cardiomyopathy at initial assessment
11 (68.8%)
Contractures
15 (93.8%)
Foot deformities
11 (84.6%)
Scoliosis and/or rigid spine
12 (80%)
Loss of ambulation at last follow-up
10 (62.5%)
Respiratory insufficiency at last follow-up
14 (93.3%)
Patients requiring ventilation
11
Restrictive cardiomyopathy at last follow-up
12 (75%)
Heart failure leading to heart transplantation
4 patients
Premature death
8 (50%), mean age 22.5 ± 9.6 years
Sudden death
5 patients
Key Findings
The recurrent BAG3 p.(Pro209Leu) variant causes a severe, homogeneous neuromuscular phenotype with early onset (mean 7.8 years).
Patients commonly present with lower limb motor weakness and restrictive cardiomyopathy, with frequent orthopedic complications such as contractures and scoliosis.
Electroneuromyography often reveals a demyelinating polyneuropathy combined with myopathy.
The disease is rapidly progressive, with most patients losing ambulation and developing respiratory insufficiency requiring ventilation by early adulthood.
High mortality (50%) occurs prematurely, frequently due to sudden death, emphasizing the severity of the cardiac involvement.
Other BAG3 variants are associated with milder neuromuscular phenotypes without significant cardiopulmonary compromise.
Clinical Implications
Clinicians should monitor patients with the BAG3 p.(Pro209Leu) variant closely for early signs of motor weakness, cardiomyopathy, and respiratory decline. Multidisciplinary management including cardiology, neurology, respiratory support, and orthopedics is essential. Awareness of the rapid progression and risk of sudden death can guide timely interventions such as heart transplantation and ventilation support.
Conclusion
This largest European cohort study delineates the severe clinical course of BAG3 p.(Pro209Leu)-related neuromuscular disease, underscoring the need for early diagnosis and comprehensive care. Milder phenotypes associated with other BAG3 variants highlight the genetic heterogeneity of BAG3-related disorders.
References
European Reference Network EURO-NMD, 2023 -- Clinical Spectrum and Long-Term Outcomes of BAG3-Related Neuromuscular Disorders in European Patients
by Gorka Fernández-Eulate, Cyril Gitiaux, Simone Thiele, Heinz Jungbluth, Anna Potulska-Chromik, Chiara Marini-Bettolo, Jean Baptiste Davion, Germán Morís, Eduard Gallardo, Montse Olivé, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Frederique Audic, Arnaud Isapof, Maggie C Walter, Corrado Angelini, Enrico Bertini, Ulrike Schara-Schmidt, Kristl G Claeys, Maike F Dohrn, Mohamed Dembele, Frédéric Fer, Guy Brochier, Teresinha Evangelista, Anna Kostera-Pruszczyk, Shahram Attarian, Volker Straub, Cristina Domínguez-González, John Vissing, Pascale Richard, Corinne Metay, Diala Khraiche, Karim Wahbi, Tanya Stojkovic
Invited narrative review supports early, interprofessional rehabilitation across the ICU recovery continuum while emphasizing heterogeneous evidence and inconsistent implementation worldwide.
