Familial Recurrent Myocarditis Triggered by Exercise in Patients With a Truncating Variant of the Desmoplakin Gene

Abstract

Background Variants of the desmosomal protein desmoplakin are associated with arrhythmogenic cardiomyopathy, an important cause of ventricular arrhythmias in children and young adults. Disease penetrance of desmoplakin variants is incomplete and variant carriers may display noncardiac, dermatologic phenotypes. We describe a novel cardiac phenotype associated with a truncating desmoplakin variant, likely causing mechanical instability of myocardial desmosomes. Methods and Results In 2 young brothers with recurrent myocarditis triggered by physical exercise, screening of 218 cardiomyopathy‐related genes identified the heterozygous truncating variant p.Arg1458Ter in desmoplakin. Screening for infections yielded no evidence of viral or nonviral infections. Myosin and troponin I autoantibodies were detected at high titers. Immunohistology failed to detect any residual DSP protein in endomyocardial biopsies, and none of the histologic criteria of arrhythmogenic cardiomyopathy were fulfilled. Cardiac magnetic resonance imaging revealed no features associated with right ventricular arrhythmogenic cardiomyopathy, but multifocal subepicardial late gadolinium enhancement was present in the left ventricles of both brothers. Screening of adult cardiomyopathy cohorts for truncating variants identified the rare genetic variants p.Gln307Ter, p.Tyr1391Ter, and p.Tyr1512Ter, suggesting that over subsequent decades critical genetic/exogenous modifiers drive pathogenesis from desmoplakin truncations toward different end points. Conclusions The described novel phenotype of familial recurrent myocarditis associated with a desmoplakin truncation in adolescents likely represents a serendipitously revealed subtype of arrhythmogenic cardiomyopathy. It may be caused by a distinctive adverse effect of the variant desmoplakin upon the mechanical stability of myocardial desmosomes. Variant screening is advisable to allow early detection of patients with similar phenotypes.

Arrhythmogenic Left Ventricular Cardiomyopathy: Genotype-Phenotype Correlations and New Diagnostic Criteria

“…These forms are often diagnosed as acute myocarditis, thus underlying the poor diagnostic accuracy of classic ACM diagnostic criteria and the need for other diagnostic tools in such cases. Recurrent episodes of acute myocarditis among family members, or a personal history of acute myocarditis combined with a family history of cardiomyopathy or SCD, should raise the suspicion of LV variants of ACM, and tissue characterization and genetic testing should be advised [56,57].…”

Myocarditis: Which Role for Genetics?

“…That is why perhaps cardiotropic viruses are more frequently identified in patients with AC than in control subjects. Interestingly, in patients with DSP mutation and recurrent myocarditis, intense physical activity has been described as another potential trigger, thus reinforcing the need to consider genomic-environment interaction [ 24 ].…”

“…Indeed, family history of cardiomyopathy, sudden cardiac death, and pacemaker implantation in early age may suggest the transmission of pathogenic genetic variants. Also, the recurrence of acute myocarditis has been recognized as a clear risk factor for underling genetic mutation [15,24]. Moreover, genetic predisposition to myocarditis is also supported by the presence of clinical traits at the physical examination (e.g., neurosensory disorders, skeletal muscle involvement, woolly hair, and keratoderma), at the laboratory analysis (e.g., creatine kinase elevation), at the ECG evaluation (e.g., persistent left bundle branch block, AV block, posterolateral pseudonecrosis, low voltage, epsilon wave), and at cardiac RMN (e.g., diffuse LGE).…”

Desmoplakin and clinical manifestations of desmoplakin cardiomyopathy

“…[ 56 ] In two young brothers with recurrent myocarditis triggered by physical exercise, screening of 218 cardiomyopathy-related genes revealed the presence of the heterozygous truncating variant p.Arg1458Ter in DSP. [ 57 ] Reichl et al [ 58 ] reported a case of a young male with acute myocarditis as the first presentation of DSP variant-associated ACM. FDG PET scans in four DSP cases revealed that acute LV myocardial injury is associated with myocardial inflammation, initially misdiagnosed as cardiac sarcoidosis or myocarditis.…”