OBJECTIVES: The purpose of this study was to examine the genotype-phenotype 
relation with respect to penetrance, age and severity of expression, disease 
progression and prognosis in a recessively inherited arrhythmogenic right 
ventricular cardiomyopathy (ARVC).
BACKGROUND: Naxos disease is a recessively inherited ARVC caused by a mutation 
in the gene encoding plakoglobin (cell adhesion protein) in which the cardiac 
phenotype is associated with palmoplantar keratoderma and woolly hair.
METHODS: Twelve families with Naxos disease underwent cardiac and molecular 
genetic investigation. Serial cardiac assessment with annual resting 12-lead and 
24-h ambulatory electrocardiogram (ECG) and two-dimensional echocardiography 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 heterozygous 
for the mutation. All adults who were homozygous (n = 26) fulfilled the 
diagnostic criteria for ARVC, the youngest by the age of 13 years. In eight 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 structural alterations and 
27% left ventricular involvement. During follow-up (10 +/- 6 years), 16 (62%) 
developed structural progression, 12 (46%) arrhythmic events and 7 (27%) heart 
failure. The annual disease-related and sudden death mortality was 3% and 2.3%, 
respectively.
CONCLUSIONS: Autosomal recessive ARVC caused by a mutation in plakoglobin was 
100% penetrant by adolescence. Affected subjects who were homozygous experienced 
progressive disease with adverse prognosis. A minority of subjects who were 
heterozygous showed minor ECG/echocardiographic changes, but clinically 
significant disease did not develop.