Disease spectrum and long-term prognosis of patients with <i>BAG3</i> -associated neuromuscular diseases in Europe
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".