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CARDIOMYOPATHY

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

Nikos Protonotarios, MD^*,* , Adalena Tsatsopoulou, MD^*, Aris Anastasakis, MD, Elias Sevdalis, MD, Godfrina McKoy, PhD, Kostas Stratos, MD, Kostas Gatzoulis, MD, Kostas Tentolouris, MD, Chara Spiliopoulou, MD, Demos Panagiotakos, PhD, William McKenna, MD, FRCP, FACC and Paulos Toutouzas, MD, FACC

^* Yannis Protonotarios Medical Center, Naxos, Greece
Department of Cardiology, University of Athens, Athens, Greece
Department of Cardiological Sciences, St. George’s Hospital Medical School, London, United Kingdom
Department of Forensic Medicine and Toxicology, University of Athens, Athens, Greece

Manuscript received February 28, 2001; revised manuscript received June 11, 2001, accepted July 11, 2001.

^* Reprint requests and correspondence: Dr. Nikos I. Protonotarios, Yannis Protonotarios, Medical Centre of Naxos, Hora Naxos 84 300, Greece
adalena{at}otenet.gr

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.

Abbreviations and Acronyms   ARVC = arrhythmogenic right ventricular cardiomyopathy   CI = confidence interval   ECG = electrocardiogram   LBBB = left bundle branch block   VT = ventricular tachycardia

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