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

Figures

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  Figure 1. Flowchart of the study and the BAG3-NMD population. (A) Flowchart of the study. (B) Map of Europe depicting centres that responded to the call. Red stars indicate centres that reported not having any BAG3-NMD patients, yellow stars indicate centres with patients who were identified but not included in the study, and green stars indicate the centres with BAG3-NMD patients who were finally included in the series. The figure was partly created in BioRender. Fernández, G. (2025) https://BioRender.com/pxrucb1. ERN EURO-NMD = European Reference Network for neuromuscular diseases; NMD = neuromuscular disease; VUS = variant of unknown significance.

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  Figure 2. Clinical presentation of BAG3-NMD patients. (A) Heat map of muscle testing using the MRC sum score (0–5) for proximal versus distal, and upper versus lower limb muscles in patients from the p.(Pro209Leu) group versus those carrying other BAG3-NMD variants; patients are ordered according to increasing time since onset of disease to muscle testing evaluation. (B) Muscle histology of p.(Pro209Leu) patients shows myopathic changes and rimmed vacuoles (haematoxylin and eosin staining), BAG3 deposits (BAG3 stain) and myofibrillar disorganization (NADH-TR and electron microscopy). (C) ECGs showing negative T waves (star-shaped symbol) and ST segment depression (arrow) in the apical, inferior and lateral leads in two p.(Pro209Leu) patients, the first with evidence for a restrictive cardiomyopathy on cardiac imaging, whereas in the second cardiac imaging was normal. (D) Cardiac MRI long-axis (4-chamber apical view) and short-axis views (top and bottom panels, respectively) from a p.(Pro209Leu) patient showing left and right atrial enlargement (circle), global left ventricular wall thickening (arrowheads) and right ventricular dilatation and thickening (star-shaped symbol). The figure was…

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  Figure 3. Muscle MRI in p.(Pro209Leu) BAG3 patients. (A) Muscle MRI T1-weighted sequences of Patients PL02 (10 years old, with preserved independent ambulation), FR03 (11 years old, loss of independent ambulation), FR01 (23 years old, complete loss of ambulation) and ES01 (32 years old, complete loss of ambulation). PL02 shows mild increased signal intensity suggestive of fatty transformation of paraspinal muscles and soleus muscles. FR03 shows moderately increased signal intensity of paraspinal and glutei muscles, muscles of the thigh (with a predominance in the posterior compartment) and the legs (particularly soleus and peroneus muscles). FR01 shows severe increased signal intensity of paraspinal and glutei muscles, muscles of the thigh with relative vastus lateralis sparing (arrowhead) and more mild leg muscle involvement, predominating in the peroneus and soleus muscles. ES01 shows diffuse end-stage increased signal intensity of paraspinal, glutei and lower limb muscles with relative sparing of vastus lateralis and gastrocnemius muscles. (B) Example of short-tau inversion recovery (STIR) hyperintensities in relatively spared muscles (stars) in patient ES01. (C) A heat map representing…

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  Figure 4. Progression of disease in BAG3-neuromuscular disease patients. (A) Kaplan–Meier and log rank test of the most important outcome events, including onset of disease, heart failure (and, in four cases, cardiac transplantation), assisted ventilation, complete loss of ambulation and overall survival. (B) Scatter plot of clinical events in p.(Pro209Leu) patients representing, for any given event, each single patient as a single point. Bars show mean age and whiskers the standard deviation. Doughnuts show the number of p.(Pro209Leu) patients with a given event out of the total number of patients for whom information was available for that event.

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  Figure 5. BAG3 gene variants. Schematic representation of the distribution on the BAG3 protein and nature of the gene variants identified in patients with neuromuscular disease in our study (top of the figure) versus those previously published by Domínguez et al.5 in patients with DCM in Europe (bottom). The main domains of the protein are indicated: the WW (tryptophan–tryptophan) domain, the two IPV (isoleucine–proline–valine) motifs, the PxxP (Pro-X-X-Pro) domain and the BAG domain. Missense variants are indicated in black, nonsense variants in red, splicing variants in orange, deletion–insertion variants in reading frame in blue, and variants resulting in a premature stop codon (frameshift following nucleotide insertions, deletions or duplications) in purple. DCM = dilated cardiomyopathy; NMD = neuromuscular disease.