Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin.
OBJECTIVE
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.
Protonotarios
N
N
Yannis Protonotarios Medical Center, Naxos, Greece. adalena@otenet.gr
Tsatsopoulou
A
A
Anastasakis
A
A
Sevdalis
E
E
McKoy
G
G
Stratos
K
K
Gatzoulis
K
K
Tentolouris
K
K
Spiliopoulou
C
C
Panagiotakos
D
D
McKenna
W
W
Toutouzas
P
P
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D017668:Age of Onset; D000368:Aged; D000704:Analysis of Variance; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D051180:Desmoplakins; D018450:Disease Progression; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D005808:Genes, Recessive / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006197:Hair / Q000002:abnormalities*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007645:Keratoderma, Palmoplantar / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008521:Mediterranean Islands / Q000453:epidemiology; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012720:Severity of Illness Index; D016019:Survival Analysis; D013575:Syncope / Q000209:etiology; D018497:Ventricular Dysfunction, Right / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D051185:gamma Catenin
D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D051185:gamma Catenin