Isolated JUP plakoglobin gene mutation with left ventricular fibrosis in familial arrhythmogenic right ventricular cardiomyopathy.

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disorder usually affecting the right ventricle (RV), characterized by fibro-fatty tissue replacement of the healthy ventricular myocardium. It often predisposes young patients to ventricular tachycardia, heart failure, and/or sudden cardiac death. However, recent studies have suggested predominantly left ventricle (LV) involvement with variable and/or atypical manifestations. Cardiac magnetic resonance (CMR) imaging has emerged as the noninvasive gold standard for the diagnosis of ARVC.

Case Summary: A 21-year-old athletic male with a family history of unknown ventricular arrhythmias, presented with near syncope, chest pain, and exertional palpitations. He had an initial work-up that was grossly unremarkable including an electrocardiogram (ECG), echocardiogram and a CMR study. Six months later, he presented again with recurrent symptoms of presyncope during exercise and his ECG demonstrated new findings of a terminal activation delay in his precordial leads. He had markedly elevated cardiac biomarkers, (troponin I > 100 ng/dl, normal value < 0.04 ng/dl) and demonstrated ventricular tachycardia with a right bundle branch morphology. An endomyocardial biopsy did not reveal any pathology. A follow-up CMR demonstrated the new development and prominent left ventricular epicardial scar in the lateral wall. The patient underwent familial genetic testing, which confirmed the presence of an isolated junction plakoglobin (JUP) gene mutation and showed multiple genes consistent with ARVC in his mother. Thus, he manifested a partial transmission of only one abnormal gene for ARVC and exhibited a markedly different expression in his disease without evidence of typical right-sided heart pathology. A third CMR study was performed, which showed partial improvement in myocardial fibrosis after exercise cessation.

Conclusion: We present a case of a young athletic male with a newly diagnosed isolated JUP gene mutation and a genetically diagnosed family history of ARVC. During his course, he demonstrated the progression of new, atypical, left ventricular fibrosis. This case demonstrates a complex interplay between genetic penetrance, phenotypical heterogeneity, and lifestyle factors such as exercise in disease progression and provides insight into the natural course of an isolated JUP mutation. Although rare, clinicians should have a high threshold for the clinical suspicion of ARVC or variants of this disorder even in the absence of classic right-sided pathologies.