emerin and Arrhythmias--Cardiac

X-linked Emery-Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers-25 familial and 5 sporadic cases-seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.

Topics: Adult; Arrhythmias, Cardiac; Asymptomatic Diseases; Cell Line, Tumor; Female; Genetic Carrier Screening; Genetic Counseling; Heart Atria; Heterozygote; Humans; Membrane Proteins; Middle Aged; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; Phenotype; X Chromosome Inactivation; Young Adult

Cardiac involvement in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) usually includes arrhythmias but not dilative cardiomyopathy (dCMP). Here, we report an X-EDMD patient with severe dCMP and life-threatening ventricular arrhythmias associated with other phenotypic features unusual for X-EDMD.. A 46-year-old patient with X-EDMD due to the known splice-site mutation c.449 + 1G>A in the emerin gene experienced palpitations for the first time at the age of 21 years, and a first syncope at the age of 23 years. He was started on phenprocoumon due to atrial fibrillation and systolic dysfunction. At the age of 28 years he received his first pacemaker. Echocardiography at the age of 36 years showed left ventricular dilatation, enlarged atria, myocardial thickening, 28% ejection fraction and diastolic dysfunction. dCMP was suspected. At the age of 38 years, a cardiac resynchronization therapy system was implanted, which was upgraded to an implantable cardioverter defibrillator (ICD) because of ventricular tachycardias (at the age of 42 years). During the following months, the ICD discharged 30 times due to ventricular tachycardias. In May 2013, he required recurrent cardio-pulmonary resuscitation because ventricular fibrillation occurred with no discharge of the ICD. He was listed for heart transplantation. He also had hypothyroidism, liver hemangiomas, thrombopenia, anemia and diverticulosis.. X-EDMD may occur along with dCMP. An ICD may be ineffective for ventricular fibrillation in X-EDMD. X-EDMD may be associated with unusual, atypical phenotypic features.

Topics: Arrhythmias, Cardiac; Cardiomyopathies; Humans; Male; Membrane Proteins; Middle Aged; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; RNA Splice Sites

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Biopsy; Contracture; Creatine Kinase; Disease Progression; DNA Mutational Analysis; Electromyography; Genetic Diseases, X-Linked; Genetic Markers; Humans; Male; Membrane Proteins; Middle Aged; Muscle Weakness; Muscle, Skeletal; Muscular Dystrophy, Emery-Dreifuss; Myocardium; Nuclear Proteins; Prognosis

The STA gene encodes emerin and is one of the genes that is affected in Emery-Dreifuss muscular dystrophy (EDMD). Although it has been reported that EDMD caused by the STA gene mutation is associated with X-linked recessive inheritance, the genotype-phenotype correlations, with special reference to cardiac manifestations, are not well defined.. We identified 16 carriers (7 male and 9 female) with a nonsense mutation in exon 6 of the STA gene in 2 EDMD families. Pacemakers were required for treatment of bradyarrhythmias in all 7 male carriers and in 2 of the 9 female carriers. In addition, 2 of the 9 female carriers displayed atrial fibrillation. In these 2 families, 3 males without pacemaker implantation, who were not tested genetically, had died suddenly. In these family members, the majority of carriers with the mutation had not been clinically diagnosed as having EDMD before genetic testing because of extremely mild or nonexistent skeletal myopathy.. EDMD caused by this mutation is characterized by atypical clinical features and incomplete penetrance of the clinical phenotype and may result in serious cardiac complications, including sudden death. Approaches to preventing possible sudden death in carriers with the STA gene mutation require further study.

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Cardiomyopathies; Child, Preschool; Codon, Nonsense; Death, Sudden, Cardiac; Family Health; Female; Heart Atria; Heart Block; Heterozygote; Humans; Incidence; Male; Membrane Proteins; Middle Aged; Muscular Dystrophy, Emery-Dreifuss; Nuclear Proteins; Pacemaker, Artificial; Pedigree; Penetrance; Phenotype; Thymopoietins

The X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is a hereditary muscle disorder associated with cardiac involvement. Sinus node dysfunction and atrioventricular conduction defects, typical of X-EDMD, occur in both males and females and may result in sudden cardiac death unless treated by permanent pacing. The objective of the study was to determine the frequency and relevance of X-EDMD in heart conduction system disease in young individuals treated with a pacemaker implant. The medical history of 3450 paced individuals in the region of South Moravia, Czech republic, was reviewed. Thirty-five patients, 20 males and 15 females, with idiopathic heart conduction disease of onset before age 40 were identified and screened for X-EDMD. Within these 35 individuals, only one male was found to carry a mutation in X-EDMD gene. We conclude that the clinical relevance of X-EDMD in heart conduction system disease is very low. It should, however, be included into the diagnostic work-up of young male individuals with idiopathic cardiac conduction disturbances.

Topics: Adolescent; Adult; Arrhythmias, Cardiac; Databases as Topic; Female; Heart Conduction System; Humans; Immunohistochemistry; Male; Membrane Proteins; Middle Aged; Mouth Mucosa; Muscle, Skeletal; Muscular Dystrophy, Emery-Dreifuss; Nuclear Proteins; Pacemaker, Artificial; Thymopoietins

Topics: Adolescent; Adult; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Child; DNA Mutational Analysis; Heart Diseases; Humans; Lamin Type A; Lamins; Membrane Proteins; Middle Aged; Muscular Dystrophies; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Proteins; Phenotype; Thymopoietins

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease characterized by early contracture of the elbows, Achilles tendons and post-cervical muscles, slow progressive muscle wasting and weakness and cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can eventually lead to sudden death. The EDMD geneencodes a novel ubiquitous protein, emerin, which decorates the nuclear rim of many cell types. Amino acid sequence homology and cellular localization suggested that emerin is a member of the nuclear lamina-associated protein family. These findings did not explain the role of emerin nor account for the skeletal muscle- and heart-specific clinical manifestations associated with the disorder. Now we report that emerin localizes to the inner nuclear membrane, via its hydrophobic C-terminal domain, but that in heart and cultured cardiomyocytes it is also associated with the intercalated discs. We propose a general role for emerin in membrane anchorage to the cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and dispensable role in association of the nuclear membrane with the lamina. In heart its specific localization to desmosomes and fasciae adherentes could account for the characteristic conduction defects described in patients.

Topics: Arrhythmias, Cardiac; Cell Adhesion; Cytoskeletal Proteins; Cytoskeleton; Desmosomes; Heart Conduction System; Humans; Membrane Proteins; Microscopy, Immunoelectron; Muscle Proteins; Muscular Dystrophies; Muscular Dystrophy, Emery-Dreifuss; Myocardium; Nuclear Envelope; Nuclear Proteins; Phosphorylation; Protein Processing, Post-Translational; Thymopoietins; X Chromosome