Clinical Profile of Four Families with Arrhythmogenic Right Ventricular Cardiomyopathy Caused by Dominant Desmoplakin Mutations

Aims: To characterize the clinical profile of patients belonging to families affected with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) due to mutations of the gene encoding for the cell-to-cell adhesion protein desmoplakin (DSP).

Methods And Results: Thirty-eight subjects belonging to four families showing different DSP mutations (three missense and one in the intron-exon splicing region) underwent clinical and genetic investigation, including annual 12-lead ECG, signal averaged ECG, 24 h Holter ECG, and two-dimensional echocardiography. Twenty-six family members (11 males and 15 females) were found to carry a DSP mutation. After a follow-up of 1-24 years, median 6, 14 (54%) fulfilled (mean age at diagnosis 33+/-15 years) and 12 (mean age 43+/-24 years at the last follow-up) did not fulfil the established diagnostic criteria of ARVC, although five of them had some cardiac abnormalities. Clinical presentations were palpitations in six, sudden death (SD) in three, syncope in one, and chest pain with increased myocardial enzymes in two. Abnormal 12-lead ECG findings were present in 15 cases (58%), ventricular arrhythmias in 12 (46%), and late potentials in 11 (42%). Fourteen (54%) had abnormal echocardiographic findings, with left ventricular involvement in seven of them. SD occurred in six subjects and in three it was the first symptom of the disease; moreover, one subject died due to heart failure. The annual disease-related death and SD/aborted SD were 0.028 and 0.023 patient/year, respectively.

Conclusion: Familial ARVC caused by DSP mutations is characterized by a high occurrence of SD even as first clinical manifestation. Left ventricular involvement is not a rare feature of the disease, which frequently escapes clinical diagnosis by applying the currently available criteria. Genetic screening is mandatory for early identification of asymptomatic carriers and preventive strategies within a family with a genotyped index case.