Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin

OBJECTIVES The purpose of this study was to examine the genotype-phenotype relation with respect to penetrance, age and severity of expression, diseas e progression and prognosis in a recessively inherited arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND Naxos disease is a recessively inherited ARVC caused by a mutati on in the gene encoding plakoglobin (cell adhesion protein) in. which the c ardiac phenotype is associated with palmoplantar keratoderma and woolly hai r. METHODS Twelve families with Naxos disease underwent cardiac and molecular genetic investigation. Serial cardiac assessment with annual resting 12-lea d and 24-h ambulatory electrocardiogram (ECG) and two-dimensional echocardi ography was performed during 1 to 16 years, median 7 +/- 6 years in all 78 surviving: members. RESULTS Twenty-eight surviving members were homozygous and 40 were heterozy gous for the mutation. All adults who were homozygous (n = 26) fulfilled th e diagnostic criteria for ARVC, the youngest by the age of 13 years. In eig ht who were heterozygous, minor ECG or echocardiographic abnormalities were observed. Of the 26 subjects who were affected homozygotes, 92% showed ECG abnormalities, 92% ventricular arrhythmias, 100% right ventricular structu ral alterations and 27% left ventricular involvement. During follow-up (10 +/- 6 years), 16 (62%) developed structural progression, 12 (46%) arrhythmi c events and 7 (27%) heart failure. The annual disease-related and sudden d eath mortality was 3% and 2.3%, respectively. CONCLUSIONS Autosomal recessive ARVC caused by a mutation in plakoglobin wa s 100% penetrant by adolescence. Affected subjects who were homozygous expe rienced progressive disease with adverse prognosis. A minority of subjects who were heterozygous showed minor ECG/ echocardiographic changes, but clin ically significant disease did not develop. (J Am Coll Cardiol 2001;38:1477 -84) (C) 2001 by the American College of Cardiology.