ARVD (Arrhythmogenic Right Ventricular Dysplasia)
or ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy)

- Genetic synopsis -

link to: Clinical synopsis - Diagnostic Criteria

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an autosomal dominant disease characterized by myocardial degeneration and fibro-fatty infiltration of the right ventricular free wall, the sub-tricuspidal region and the outflow tract. A rare autosomal recessive variant characterized by the typical myocardial involvement, palmar keratosis and wholly hairs and inherited as a recessive trait has been also described. This latter disorder is also called the Naxos disease and is one of the few variants of ARVD for which the causative gene has been identified

The estimated prevalence of ARVC ranges from 6 per 10,000 in the general population to 4.4 per 1,000 in some areas with higher prevalence. For example the Veneto region of northern Italy seems to present an unusually high prevalence of the disease; in this country several large kindred have been identified and allowed to established linkage to several loci. Two linkage studies performed in North American families mapped on different and novel loci. Overall nine genetic loci are known. For three of them, the autosomal dominant ARVD2 (1) and ARVD8 (2) and the autosomal recessive NAXOS1 (3) the corresponding gene has been identified (Table)

Desmoplakin (DSP), identified in a single ARVD8 family, and Plakoglobin (JUP), causing NAXOS1, are major constituents of the desmosomes and the intermediate junctions. They link the cytoskeleton by binding the intermediate filaments, to the plasmalemma and adjacent cells. Mutations in genes encoding for Desmoplakin and Plakoglobin suggest that altered integrity at cardiac myocyte cell-cell junctions may promote myocyte degeneration and death. Interestingly the pathogenetic mechanisms of right ventricle dilatation likely to be involved in these variants appear similar to those of dilated cardiomyopathy due to abnormalities in cytoskeletal proteins.

The third ARVC gene (locus: ARVD2) is the cardiac ryanodine receptor, RyR2 (see CPVT session for details). ARVD2 constitutes a rare and clinically atypical or "concealed" form of arrhythmogenic right ventricular dysplasia and presents exercise induces bi-directional VT very similar to those of CPVT. It is still a matter of debate whether such patients fulfill the diagnostic criteria for ARVD.

Few patients with ARVC have been successfully genotyped so far, and the above mentioned genes account for a minority of the clinically affected patients. If we consider that apoptosis (4) and inflammation (5) may play a role in ARVC pathogenesis, it is rational to hypothesize that only a fraction of ARVC cases could be determined by a single gene mutation. Some cases might be due to environmental factors (e.g. viral myocarditis) acting on a vulnerable substrate, that, in turn, may be determined by several genetic factors (SNPs), thus setting the picture of a polygenic disease. 

In November 2004 Gerull et al. (6) reported a novel locus for ARVC (ARVD9) and found mutations in 32 of 120 unrelated individuals in the PKP2 gene, which encodes plakophillin-2, an essential armadillo-repeat protein of the cardiac desmosome. This is the highest number of mutations ever reported in a single ARVC gene, thus suggesting the plakophyllin may ba a frequent cause of disease.

link to: Clinical Data

References

1. Tiso N, Stephan D, Nava A. Identification on mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum.Mol.Genet. 2001;10:189- 194.
2. Rampazzo A, Nava A, Malacrida S et al.  Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum.Genet. 2002;71:1200-1206.
3. Coonar AS, Protonotarios N, Tsatsopoulou A et al.  Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation 1998;97:2049-2058.
4. Valente M, Calabrese F, Thiene G et al.  In vivo evidence of apoptosis in arrhythmogenic right ventricular cardiomyopathy. Am J Pathol. 1998;152:479-484.
5. Basso C, Thiene G, Corrado D et al.  Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis? Circulation 1996;94:983-991.
6. Gerull B, Heuser A, Wichter T et al Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy; Nat Genet. 2004;36:1162-4.

Genetic loci and genes involved in Arrhythmogenic Right Ventricular Cardiomyopathy

allelic to CPVT1; ** allelic to DCWHK (OMIM: 605676 ); RV = right ventricular;