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 non-invasive 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, electrocardiography (ECG), echocardiography and CMR imaging. Six months later, he presented again with recurrent symptoms during exercise and his ECG demonstrating a new epsilon wave. He had markedly elevated cardiac biomarkers, (troponin I >100 ng/dl, normal value < 0.04 ng/dl). A subsequent coronary angiogram was performed, which was normal. Holter monitoring further showed subsequent episodes of ventricular tachycardia with a right bundle branch morphology. An endomyocardial biopsy was performed, which was negative. 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 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 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 a characteristic epsilon wave on ECG and the presence of new, atypical, left ventricular fibrosis on repeat CMR imaging. This case demonstrates a complex interplay between variable genetic penetrance, phenotypical heterogeneity, and lifestyle factors including exercise, in his disease expression and provides insight on the natural course of an isolated JUP mutation. Although rare, clinicians should have a high threshold for the suspicion of ARVC or variants of this disorder even in the absence of classic right sided pathologies and /or an initially normal work-up.