ABSTRACT
Introduction
Hereditary inclusion body myopathy (hIBM) refers to a group of clinically and genetically heterogeneous diseases. The overlapping histochemical features of hIBM with other ...genetic disorders lead to low diagnostic rates with targeted single‐gene sequencing. This is true for the most prevalent form of hIBM, GNEpathy. Therefore, we used whole‐exome sequencing (WES) to determine whether a cohort of clinically suspected GNEpathy patients undiagnosed by targeted GNE analysis could be genetically characterized.
Methods
Twenty patients with hIBM but undiagnosed by targeted GNE sequencing were analyzed by WES before data filtering on 306 genes associated with neuromuscular disorders.
Results
Seven patients out of 20 were found to have disease‐causing mutations in genes associated with hIBM or genes allowing for hIBM in the differential diagnosis or associated with unexpected diagnosis.
Discussion
Next‐generation sequencing is an efficient strategy in the context of hIBM, resulting in a molecular diagnosis for 35% of the patients initially undiagnosed by targeted GNE analysis. Muscle Nerve 56: 993–997, 2017
Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to ...adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (Median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never aquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (Median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (Median: 7 years, range 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopedic, cardiac, and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.
The diagnosis of Emery–Dreifuss muscular dystrophy (EDMD) is suggested by the combination of musculoskeletal weakness and wasting, joint contractures, and cardiac disease. Herein we report a patient ...in whom an ischemic stroke prompted the diagnosis of EDMD. A mutation in the LMNA gene (c.266G>T, p.Arg89Leu) was found. It had been reported previously exclusively with isolated cardiac disease, thus reinforcing the high phenotypic heterogeneity of laminopathies. Muscle Nerve, 2011
The latest practice guidelines from the American College of Cardiology/American Heart Association recommend the prescription of an ACE-i for patients presenting with non-ischemic cardiomyopathy when ...left ventricular ejection fraction (LVEF) falls below 40%.
To determine if the initiation of treatment with an angiotensin-converting enzyme inhibitor (ACE-i) earlier than recommended by practice guidelines issued by professional societies improves the long-term cardiac outcomes of patients presenting with Becker muscular dystrophy (MD) cardiomyopathy.
From a multicenter registry of Becker MD, we selected retrospectively patients presenting between January 1990 and April 2019 with a LVEF ≥40 and ≤49%. We used a propensity score analysis to compare the risk of a) hospitalization for management of heart failure (HF), and b) a decrease in LVEF to <35% in patients who received an ACE-i when LVEF fell below 40% (conventional treatment), versus below 50% (early treatment).
From the 183 patients entered in our registry, we identified 85 whose LVEF was between 40 and 49%, 51 of whom received early and 34 received conventional ACE-i treatment. Among patients with early versus conventional treatments, 2 (3.9%) versus 4 (11.8%) were hospitalized for management of HF hazard ratio (HR) 0.151; 95% confidence interval (CI) 0.028 to 0.822; p = 0.029, and 9 (17.6%) versus 10 (29.4%) had a decrease in LVEF below 35% (HR 0.290; 95% CI 0.121 to 0.694; p = 0.005).
The long-term cardiac outcome of patients presenting with Becker MD was significantly better when treatment with ACE-i was introduced after a decrease in LVEF below 50%, instead of below 40% as recommended in the current practice guidelines issued by professional societies.
The mechanisms underlying cell response to mechanical forces are critical for muscle development and functionality. We aim to determine whether mutations of the LMNA gene causing congenital muscular ...dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts (LMNA) embedded in soft matrix did not align along the gel axis whereas control myoblasts did. LMNA myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft 2D and/or static 3D conditions, LMNA myoblasts demonstrated enhanced activation of Yes-Associated Protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. SiRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in lamin A/C mutated myoblasts.
BACKGROUND:An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable ...cardioverter-defibrillator implantation.
METHODS:We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians interquartile range.
RESULTS:We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 1.0–7.2 and 5.1 2.0–9.3 years of follow-up, respectively. Predictors of LTVTA in the derivation sample weremale sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach.
CONCLUSIONS:In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT03058185.
In front of the wide clinical and genetic heterogeneity of the laminopathies, the first task of the French Network on EDMD and other related nuclear envelope related diseases, has been to set up in ...2000, a mutation database for LMNA and EMD mutations. We selected the Universal Mutation Database tool (UMD) developed by Christophe Beroud (www.umd.be,1) and set up the UMD-LMNA database that compiles genetic and associated main clinical features of both in-house identified cases, those submitted to us by other partners involved in LMNA gene analysis, and also all mutated subjects reported in the literature (www.umd.be/LMNA/). To date, the UMD-LMNA database comprises 510 different LMNA mutations identified in over 2700 individuals, out of which 60% presenting with a laminopathy of the striated muscles (cardiomyopathies+/-muscular dystrophies), 14% with a laminopathy affecting the adipose tissue (metabolic syndromes +/- partial lipodystrophies) and 5.2% with premature ageing syndrome.
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