Cardiac Emerinopathy

Abstract

Background: Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. Methods: Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). Results: We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. Conclusions: Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.

Excessive Trabeculation of the Left Ventricle

“…Excessive trabeculation has been observed in several neuromuscular disorders, including specific genetically determined conditions such as Barth syndrome, 69 mitochondrial disorders, 70 nuclear envelopathies, 71 dystrobrevinopathy, 72 myotonic dystrophy, zaspopathy, 73 and myoadenylate deaminase deficiency, 74 as well as Duchenne and Becker types of muscular dystrophy. 75 A causal relationship with the underlying genetic defects, however, has yet to be established, with genotypic-phenotypic heterogeneity largely unexplained.…”

Emery–Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure

“… 19 , 23 In our study, LVSD was observed in just under half of all male EMD variant-carriers, and 13% developed ESHF suggesting that regular monitoring of left ventricular function should be routine. It was also notable that over a quarter of male EMD variant-carriers with cardiac involvement had no reported neuromuscular disease, supporting recent work by Ishikawa et al 24 who suggested the term ‘cardiac emerinopathy’ to describe those patients with an isolated cardiac phenotype.…”

Nucleus Mechanosensing in Cardiomyocytes

“…They are known to bind to the lamina, provide structural integrity, and communicate mechanical cues, thereby participating in signal transduction pathways. Variants of proteins such as emerin, nesprin-1 and 2, lamin A/C, and LAP1 and LAP2 have been reported to be associated with pathological cardiac development and muscular dystrophy [24,29,[42][43][44][45]. The communication of cytoskeleton tension forces is therefore supported by the nuclear envelope proteins, which is particularly important within myocytes.…”