High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation

We studied 54 Living relatives from a large French kindred, among which 17 members presented with a cardiomyopathy transmitted on an autosomal dominan t mode. Five of these individuals had clinical manifestations of muscle dis ease phenotypically consistent with Emery-Dreifuss muscular dystrophy. Gene tic analysis of this kindred had demonstrated a nonsense mutation in the LM NA gene located on chromosome 1q11-q23. This gene encodes lamins A and C, p roteins of the nuclear lamina located on the inner face of he nuclear envel ope. We retrospectively determined the cause of death of 15 deceased family members, 8 of whom had died suddenly, 2 as a first and single manifestatio n of the disease. The six other cases had histories of arrhythmias and left ventricular dysfunction before dying suddenly, and three of them died desp ite the prior implantation of a permanent pacemaker. The mean age of onset of cardiac symptoms among affected living family members was 33 years (rang e 15-47 years), and the first symptoms were due to marked atrioventricular conduction defects or sinus dysfunction, requiring the implantation of perm anent pacemakers in seven cases. Myocardial dysfunction accompanied by vent ricular arrhythmias developed rapidly in the course of the disease and resu lted in severe dilated cardiomyopathy requiring cardiac transplantation in three cases. In conclusion; in patients presenting a life-threatening famil ial or sporadic cardiac restricted phenotype similar to that described here , mutations in the lamins A and C gene should be looked for. in the genotyp ically affected individuals, cardiological and electrophysiological follow- up should be performed to prevent sudden death that could occur rapidly in the evolution of such disease.