The molecular genetics of arrhythmogenic right ventricular dysplasia-cardiomyopathy.

Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD or ARVC) is an inherited disorder characterized by replacement of the right ventricular myocardium by adipose and fibrous tissue and associated with sudden cardiac death. This disorder may be as prevalent as 6 in 10 000 and causes 12.5%-25% of sudden death events in the young. Nine genetic loci associated with this disease have been ascertained, and mutations in genes at 3 loci have been discovered. These genetic studies have shed light on some of the pathogenetic mechanisms. Mutations in genes encoding desmoplakin and plakoglobin suggest that altered integrity at cardiac myocyte cell-cell junctions may promote myocyte degeneration and death, with the repair process consisting of replacement of myocardium by adipose and fibrous tissue. Mutations in the gene encoding the cardiac ryanodine receptor suggest that cytoplasmic calcium overloading may lead to arrhythmias characteristic of ARVD, and perhaps also the structural changes. Many of the remaining questions concerning the pathogenesis of ARVD can be answered only by the mapping and identification of other genes associated with this disease.