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

Category	Detail
Condition	BAG3-related neuromuscular disorders including myofibrillar myopathy, Charcot–Marie–Tooth disease, and cardiomyopathy
Key Mechanisms	Autosomal dominant or de novo BAG3 gene variants affecting skeletal and cardiac muscle via impaired protein quality control and chaperone-assisted selective autophagy
Target Population	European pediatric and adult patients with BAG3 pathogenic variants
Care Setting	Specialized neuromuscular reference centers in Europe

The recurrent BAG3 c.626C>T p.(Pro209Leu) variant causes a severe, rapidly progressive neuromuscular and cardiac phenotype with early onset (~7.8 years).
Patients with p.(Pro209Leu) variant frequently develop lower limb weakness, restrictive cardiomyopathy, respiratory insufficiency, and orthopedic deformities leading to loss of ambulation and high mortality.
Other BAG3 variants are rare and associated with milder disease courses without significant cardiorespiratory involvement.

Confirm neuromuscular disease clinically and with electroneuromyography or muscle histology.
Perform genetic testing for pathogenic or likely pathogenic BAG3 variants in suspected cases.

Monitor cardiac function closely due to high risk of restrictive cardiomyopathy and heart failure.
Provide respiratory support as needed, including ventilation for respiratory insufficiency.
Orthopedic management for contractures, foot deformities, scoliosis, and rigid spine.
Consider heart transplantation in advanced cardiomyopathy cases.

Regular follow-up for motor function to detect loss of ambulation.
Cardiac surveillance for restrictive cardiomyopathy progression and heart failure.
Respiratory function monitoring to identify onset of insufficiency.

High risk of premature death, often sudden, especially in patients with p.(Pro209Leu) variant.
Rapid disease progression leading to loss of ambulation and multi-organ involvement.

European patients with BAG3-related neuromuscular disorders, predominantly those with p.(Pro209Leu) variant

No approved treatments currently; preclinical studies suggest potential benefit of metformin and gene therapy approaches under development.

Early genetic diagnosis to inform prognosis and guide multidisciplinary care.
Comprehensive cardiac and respiratory assessment at diagnosis and during follow-up.
Multidisciplinary management including neurology, cardiology, pulmonology, and orthopedics.
Patient counseling regarding disease progression and risks of sudden death.
Participation in clinical trials or registries to advance understanding and treatment.

Clinical Scorecard: Clinical Spectrum and Long-Term Outcomes of BAG3-Related Neuromuscular Disorders in European Patients