High Incidence of Sudden Death with Conduction System and Myocardial Disease Due to Lamins A and C Gene Mutation

Abstract

We studied 54 living relatives from a large French kindred, among which 17 members presented with a cardiomyopathy transmitted on an autosomal dominant mode. Five of these individuals had clinical manifestations of muscle disease phenotypically consistent with Emery-Dreifuss muscular dystrophy. Genetic analysis of this kindred had demonstrated a nonsense mutation in the LMNA gene located on chromosome 1q11-q23. This gene encodes lamins A and C, proteins of the nuclear lamina located on the inner face of the nuclear envelope. We retrospectively determined the cause of death of 15 deceased family members, 8 of whom had died suddenly, 2 as a first and single manifestation of the disease. The six other cases had histories of arrhythmias and left ventricular dysfunction before dying suddenly, and three of them died despite the prior implantation of a permanent pacemaker. The mean age of onset of cardiac symptoms among affected living family members was 33 years (range 15-47 years), and the first symptoms were due to marked atrioventricular conduction defects or sinus dysfunction, requiring the implantation of permanent pacemakers in seven cases. Myocardial dysfunction accompanied by ventricular arrhythmias developed rapidly in the course of the disease and resulted in severe dilated cardiomyopathy requiring cardiac transplantation in three cases. In conclusion, in patients presenting a life-threatening familial or sporadic cardiac restricted phenotype similar to that described here, mutations in the lamins A and C gene should be looked for. In the genotypically affected individuals, cardiological and electrophysiological follow-up should be performed to prevent sudden death that could occur rapidly in the evolution of such disease.

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

“…In this series of patients, who were implanted with a defibrillator in 59% of cases, male sex, non-missense mutations, and left ventricular dysfunction were associated with development of sustained ventricular tachyarrhythmias, while no relationship was found with the mode of presentation (with isolated or combination of clinical features) [24]. These findings are in line with a previous multicentre study, where a series of risk factors emerged as predictors of the occurrence of ventricular tachyarrhythmias (male gender, non- sustained ventricular tachycardia, left ventricular ejection fraction <45% and non-missense mutation), thus providing an important clinical guide for the decision to implant an ICD [53] (Table 2) [4,6,23,24,27,43,44,47,51–62]…”

“…A detailed review of all the literature published on the risk of ventricular tachyarrhythmias, and on device activations in carriers of an implantable cardioverter defibrillators (ICDs) are shown in Table 2, in relationship to the series of patients with laminopathies reported in Table 1 [4,6,23,24,27,43,44,47,51–62]. In the largest observational study, reported by Kumar et al [24], the cumulative occurrence of sustained ventricular tachyarrhythmias was 34% at 7 years, and among patients with no history of ventricular tachyarrhythmias the incidence was 22% during a 7-year follow-up.…”

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

“…Although a skeletal myopathy predominates in two of these disorders, some patients develop cardiac electrophysiologic disease, progressive left ventricular dysfunction and heart failure (11). Electrophysiologic defects usually precede DCM (12), and may be the only manifestation of cardiac involvement (13)]. Electrophysiologic abnormalities include sinus node dysfunction, progressive atrioventricular (AV) block, paroxysmal atrial fibrillation and ventricular arrhythmias [9,10,14].…”

“…Several mutations which should produce null alleles cause Emery-Dreifuss muscular dystrophy. While most missense mutations associated with these cardiac phenotypes are predicted to encode dominant negative alleles, at least one mutation [17] predicted to produce haploinsufficiency, causes familial DCM and conduction system disease [8,9,10,12,13].…”

Significance of sarcomere gene mutation in patients with dilated cardiomyopathy

“…LMNA geneencoded protein products include lamin A and C, which are important components of the nucleus fiber layer and are the main cytoskeleton protein for maintaining normal nuclear membrane morphology. It has been confirmed that the first symptom of DCM induced by LMNA gene mutation is severe arrhythmia, whereas decreased heart function often appears late but progresses quickly in these patients (Bécane et al, 2000). However, in this study, most patients with IDCM were diagnosed with decreased ventricular function and heart ultrasonic LVEF was considered as an evaluation criterion.…”