Desmoplakin disease in arrhythmogenic right ventricular cardiomyopathy: early genotype–phenotype studiesThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Abstract

This editorial refers to ‘Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations’† by B. Bauce et al. , on page 1666 Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in ventricular arrhythmia and sudden death. Myocyte loss with fibrofatty replacement is the typical pathological finding, with inflammatory infiltrates in up to 67% of cases.1 Insight into the pathogenesis of ARVC awaited identification of the first disease-causing gene, plakoglobin, in a recessive variant of ARVC known as Naxos disease.2 Naxos disease is distinguished from the more common autosomal dominant disease form by the presence of palmoplantar keratoderma and woolly hair in all genetically affected individuals. Plakoglobin is a key component of desmosomes, the specialized intercellular junctions of cardiac and epithelial tissues. Desmosomes provide mechanical coupling between the intermediate filaments and the cytoplasmic membranes of adjacent cells. Tissue exposed to shear or frictional stress is dependent on the strength of this supporting network. A defect in a major desmosomal component may compromise its adhesive function, pre-disposing to cellular detachment and death. Significant myocyte necrosis may be accompanied by an inflammatory response. The regenerative capacity of the myocardium is limited, necessitating repair by fibrofatty substitution. The identification of plakoglobin as the cause of Naxos disease paved the way for the search for other desmosomal mutations. Shortly thereafter, a homozygous mutation in desmoplakin was isolated in Carvajal disease, a cardiocutaneous syndrome bearing close resemblance to Naxos disease, with two exceptions: early and prominent left ventricular involvement and pure fibrosis without adipose replacement.3 In 2002, Rampazzo et al. 4 reported a missense mutation in desmoplakin (S299R) in a large Italian family with autosomal dominant ARVC. The subsequent recognition that mutations in plakophilin-2 are common in ARVC lent further support to … *Corresponding author. Tel: +44 020 7573 8841; fax: +44 020 7573 8838. E-mail address : william.mckenna{at}uclh.org