Monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin gene variant

Abstract

Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST-T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene [NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9)] that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.

Genetic Background and Clinical Features in Arrhythmogenic Left Ventricular Cardiomyopathy: A Systematic Review

“…The full-text screening of these articles led to the exclusion of 56 studies due to their compliance with the inclusion/ exclusion criteria. The remaining 31 articles were considered eligible for this review [ 10 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ] A PRISMA flow diagram depicts the flow of information through the different literature review phases ( Figure 1 ). Our inclusion criteria, with regard to the presence of detailed patients’ clinical features, led to the exclusion of several publications reporting a significant number of subjects.…”

Arrhythmogenic Right Ventricular Cardiomyopathy Accompanied by Chronic Myocarditis

“…To our knowledge, only two patients have been reported to have desmoglein-2 mutation, presenting with ARVC and concomitant biventricular myocarditis (5,10). It seems that the clinical presentation, including LV involvement, cannot be explained simply by the type of gene mutation (10), although desmoplakin mutation carriers mostly develop LV involvement (2,5,6).…”

“…Recently, myocardial inflammation has been considered to be involved in the pathogenesis of ARVC (5). Several case reports have described patients with ARVC initially presenting with clinical acute or recurrent myocarditis and predominantly showing left ventricular abnormalities (1,5,6). However, there have been a few reports of cases presenting with right ventricular abnormalities with chronic myocarditis in advanced-stage ARVC (7).…”

Inflammation in the Pathogenesis of Arrhythmogenic Cardiomyopathy: Secondary Event or Active Driver?

“…The first study establishing a link between genetics and viral susceptibility in ACM patients showed that family members carrying the same causative rare variant in the DSP gene seemed to be particularly vulnerable to develop viral myocarditis (116). Recently, some reports have also suggested the relation between DSP mutations and a family history of recurrent myocarditis (117,118). In another study, genetic analysis on three cases of myocarditis-related SCD and their family members revealed the presence of rare novel variants predicted as deleterious and potentially pathogenic in ACM-related genes (PKP2, DSP DSC2, and TTN) (115), also including DSP as a crucial gene involved.…”