Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2.
BACKGROUND
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by right ventricular dysfunction and ventricular arrhythmias. A recent study reported mutations in PKP2, encoding the desmosomal protein plakophilin-2, associated with ARVD/C. The purpose of our study was to validate the frequency of PKP2 mutations in another large series of ARVD/C patients and to examine the phenotypic characteristics associated with PKP2 mutations.


RESULTS
DNA from 58 ARVD/C patients was sequenced to determine the presence of mutations in PKP2. Clinical features of ARVD/C were compared between 2 groups of patients: those with a PKP2 mutation and those with no detectable PKP2 mutation. Thirteen different PKP2 mutations were identified in 25 (43%) of the patients. Six of these mutations have not been reported previously; 4 occurred in multiple, apparently unrelated, families. The mean age at presentation was lower among those with a PKP2 mutation (28+/-11 years) than in those without (36+/-16 years) (P<0.05). The age at median cumulative symptom-free survival (32 versus 42 years) and at the median cumulative arrhythmia-free survival (34 versus 46 years) was lower among patients with a PKP2 mutation than among those without a PKP2 mutation (P<0.05). Inducibility of ventricular arrhythmias on an electrophysiology study, diffuse nature of right ventricular disease, and presence of prior spontaneous ventricular tachycardia were identified as predictors of implanted cardioverter/defibrillator (ICD) intervention only among patients without a PKP2 mutation (P<0.05).


CONCLUSIONS
Our study highlights the clinical relevance of PKP2 mutations in ARVD/C. Presence of a PKP2 mutation in ARVD/C correlates with earlier onset of symptoms and arrhythmia. Patients with a PKP2 mutation experience ICD interventions irrespective of the classic risk factors determining ICD intervention in ARVD/C patients.
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Darshan
D
Dalal
Lorraine H
LH
Molin
Jonathan
J
Piccini
Crystal
C
Tichnell
Cynthia
C
James
Chandra
C
Bomma
Kalpana
K
Prakasa
Jeffrey A
JA
Towbin
Frank I
FI
Marcus
Philip J
PJ
Spevak
David A
DA
Bluemke
Theodore
T
Abraham
Stuart D
SD
Russell
Hugh
H
Calkins
Daniel P
DP
Judge
D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051191:Plakophilins / Q000235:genetics*; D016019:Survival Analysis
C495337:PKP2 protein, human; D051191:Plakophilins