emerin and Atrial-Fibrillation

Emery-Dreifuss muscular dystrophy is an early-onset, slowly progressive myopathy characterized by the development of multiple contractures, muscle weakness and cardiac dysfunction. We present here the case of a 65-year-old male patient with a 20 year history of slowly progressive camptocormia, bradycardia and shortness of breath. Examination showed severe spine extensor and neck flexor muscle weakness with slight upper limb proximal weakness. Cardiologic assessment revealed slow atrial fibrillation. Whole body MRI demonstrated adipose substitution of the paravertebral, limb girdle and peroneal muscles as well as the tongue. Emerin immunohistochemistry on patient muscle biopsy revealed the absence of nuclear envelope labeling confirmed by Western Blot. Genetic analysis showed a hemizygous duplication of 5 bases in exon 6 of the EMD, emerin, gene on the X chromosome. This is an unusual presentation of X-linked Emery-Dreifuss muscular dystrophy with adult onset, predominant axial muscles involvement and minimal joint contractures. Diagnosis was prompted by the analysis of emerin on muscle biopsy.

Topics: Age of Onset; Aged; Atrial Fibrillation; Back Muscles; Bradycardia; Contracture; Deltoid Muscle; Dyspnea; Hamstring Muscles; Humans; Magnetic Resonance Imaging; Male; Masticatory Muscles; Membrane Proteins; Muscle, Skeletal; Muscular Atrophy, Spinal; Muscular Dystrophy, Emery-Dreifuss; Nuclear Proteins; Severity of Illness Index; Spinal Curvatures

We reviewed recent advancements in the relationship between sinus node dysfunction (SND) and atrial fibrillation (AF) and propose some underlying mechanisms in regard to ion and molecular aspects. The amount of clinical and animal experiments have proven the structural and electrophysiological remodeling of sinoatrial node (SAN) and atrium may be related significantly between SND and AF. Atrial remodeling was often related to RAS activation. RAS inhibitors and statin, which resist in atrial fibrosis, may be novel strategies to prevent or treat both SND and AF. Besides, funny current (If) and Ca(2+) clock mainly contributing to the SAN automaticity may be another link between SND and AF. Gap junctions such as Cx40, Cx43 and Cx45 were proven to participate in both automaticity and conductivity of electrical impulses in SAN and atrial tissue, which was accepted as another link between SND and AF. Common genetic mutations such as the emerin gene, SCN5A gene and HCN4 gene mutation were also the mechanism for the correlation between SND and AF.

Topics: Animals; Atrial Fibrillation; Atrial Remodeling; Gap Junctions; Heart Conduction System; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Membrane Proteins; Models, Cardiovascular; Muscle Proteins; NAV1.5 Voltage-Gated Sodium Channel; Nuclear Proteins; Potassium Channels; Sick Sinus Syndrome; Sinoatrial Node

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

Atrial fibrillation (AF) is a heritable disorder with male predilection, suggesting a sex chromosome defect in certain patients. Loss-of-function truncation mutations in EMD, encoding the nuclear membrane protein emerin, cause X-linked Emery-Dreifuss muscular dystrophy (EDMD) characterized by localized contractures and skeletal myopathy in adolescence, sinus node dysfunction (SND) in early adulthood, and atrial fibrillation as a variably associated trait. This study sought to identify the genetic basis for male-restricted, nonsyndromic sinus node dysfunction and AF in a multigenerational family.. Genealogical and medical records, and DNA samples, were obtained. Progressive SND and AF occurred in four males related through maternal lineages, consistent with X-linked inheritance. Skeletal myopathy was absent, even at advanced ages. Targeted X chromosome genotyping mapped the disease locus to Xq28, implicating EMD as a positional candidate gene. DNA sequencing revealed hemizygosity for an in-frame 3-bp deletion in EMD (Lys37del) in affected males, disrupting a residue within the LEM binding domain critical for nuclear assembly but leaving the remainder of the protein intact. Buccal epithelial cell staining with emerin antibody demonstrated near-total functional loss of emerin. Female relatives underwent prospective electrocardiographic and genetic testing. Those heterozygous for Lys37del had approximately 50-70% emerin-positive nuclei and variable degrees of paroxysmal supraventricular arrhythmia.. Mutation of EMD can underlie X-linked familial AF. Lys37del is associated with epithelial cell emerin deficiency, as in EDMD, yet it causes electrical atriomyopathy in the absence of skeletal muscle disease. Targeted genetic testing of EMD should be considered in patients with SND-associated AF and/or family history suggesting X-linked inheritance.

Topics: Adult; Atrial Fibrillation; Genetic Diseases, X-Linked; Genetic Predisposition to Disease; Heterozygote; Humans; Male; Membrane Proteins; Middle Aged; Mutation; Nuclear Proteins; Pedigree; Sinoatrial Node

Topics: Adult; Atrial Fibrillation; Genetic Diseases, X-Linked; Genetic Predisposition to Disease; Heterozygote; Humans; Male; Membrane Proteins; Middle Aged; Nuclear Proteins; Pedigree; Sinoatrial Node