Clin Genet 2015: 88: 502–504 Printed in Singapore. All rights reserved
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12578
Letter to the Editor
Extreme variability in clinical penetrance for a splice-site Plakophilin-2 mutation in a Bangladeshi family To the Editor: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/ARVD) is a relatively rare form of cardiomyopathy and a leading cause of sudden cardiac death in young adults (1). Mutations in the desmosomal genes are usually described, of which PKP2 mutation is the most prevalent with familial inheritance noted in about 50% of cases (2). At present, there is no definitive treatment for ARVC/ARVD but beta blockers are considered to have some efficacy to ameliorate the symptoms, and ICD implantation is recommended for secondary prevention (1). We first report a case of ARVC/ARVD from Bangladesh with its genotype and extended clinical and genetic surveillance among the family members. A 39-year-old male, elementary school teacher was admitted at Rajshahi Medical College Hospital, Bangladesh, with restlessness and panicky apprehended state in June 2012. He had recurrent palpitation with mild chest discomfort and a few episodes of dizziness followed by syncope. On examination, his blood pressure (BP) was 80/60 mmHg with rapid and thready pulse but lung bases were clear. Electrocardiogram (ECG) revealed a sustained monomorphic ventricular tachycardia (VT) of LBBB morphology with superiorly placed QRS axis (Fig. 1a,b). Initially, intravenous (IV) amiodarone failed to restore the sinus rhythm and eventually direct current (DC) cardioversion was needed. Sinus ECG revealed a typical epsilon wave in V1 with prolonged terminal activation duration along with T-wave inversion in the absence of RBBB in V1−V3 (Fig. 1c). On the following day, patient had multiple recurrences of monomorphic VT despite having adequate anti-ischemic and anti-arrhythmic medications that persisted for about 48 h when he finally became stabilized with either DC cardioversion and/or IV amiodarone. Coronary angiogram showed normal coronary arteries and no evidence of ischemia. Based on the revised task force criteria (epsilon wave, negative T wave in V1–V3, VT with LBBB morphology and superior axis), patient was clinically diagnosed as ARVC/ARVD. ICD implantation was advised, but patient declined because of financial incapacity. He was discharged with sotalol, 80 mg twice daily to be continued and periodic follow-up. Over 2 years follow-up, he was found reasonably well without any further recurrence of VT. But suddenly
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he succumbed during sleep after 2.5 years of initial presentation. Analysis of desmosomal genes revealed a previously described (3) splice-site mutation 2490-1G > C, in the PKP2 gene, with a putative amino acid change of p.Asp829Glyfs2 (Fig. 1d). Mutation was also found in his youngest brother, but the father was negative. His mother, a 72-year-old asymptomatic lady was found positive for the mutation. Subsequent screening of the family members revealed additional five members positive for the mutation (two sisters, one maternal uncle, an aunt and one niece) (Fig. 1e). All mutation carriers (n = 7) were followed up for over a year through ECG, echocardiogram, exercise testing and 24-h ambulatory ECG monitoring. Male mutation carriers, i.e., proband’s youngest brother and second-degree maternal uncle complained a few episodes of palpitations, and their ECG showed early repolarization changes, but all females carriers were asymptomatic with normal ECGs. Cardiac MRI and SAECG could not be carried out due to lack of facility. The proband first expressed his phenotype at 39 years and died at 41 years, but his mother, through whom the mutation was transmitted, is still asymptomatic even at the age of 72 years. Such a long quiescent state can be explained with the non-penetrance phenotype of ARVC/ARVD in many cases, also family screening showed reduced penetrance and variable expressivity which are consistent with the natural course of PKP2 mutations (4). To our knowledge, this is the first genetic study of a family of ARVC/ARVCD with PKP2 mutation in Bangladesh where interesting genotype phenotype correlations are noted. This report indicates the presence of this rare arrhythmogenic cardiomyopathy in our population and demands further study to figure out its prevalence. Acknowledgement Dr. Z. A. B. is supported by a research grant from the Foundation Suisse de Cardiologie/number: 59283.
M.Z. Sayeeda M.A. Salamb A.K.M. Monwarul Islamc
Fig. 1. (a, b) Echocardiography (ECG) on admission showing VT with left bundle branch block (LBBB) morphology with superiorly placed QRS axis. (c) Arrowheads showing epsilon wave in lead V1 after direct-current (DC) cardioversion and prolonged terminal activation duration with T-wave inversion in right precordial leads without right bundle branch block (RBBB). (d) Splice acceptor site mutation in PKP2 gene in the intron 12 and exon 13 junctions. (e) Pedigree of the family with PKP2 mutation.
Letter to the Editor
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Letter to the Editor Z.A. Bhuiyand of Cardiology, Rajshahi Medical College, Rajshahi 6000, Bangladesh b Department of Microbiology, Rajshahi Medical College, Rajshahi 6000, Bangladesh c Department of Cardiology, Jessore Medical College, Jessore, Bangladesh d Laboratoire de Diagnostic Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland a Department
References 1. Marcus FI, McKenna WJ, Sherrill D et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 2010: 121: 1533–1541.
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2. Kannankeril PJ, Bhuiyan ZA, Darbar D, Mannens MM, Wilde AA, Roden DM. Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: wide spectrum of disease in mutation carriers within a family. Heart Rhythm 2006: 3: 939–944. 3. Gerull B, Heuser A, Wichter T et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004: 36: 1162–1164. 4. Van Tintelen JP, Entius MM, Bhuiyan ZA et al. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation 2006: 113: 1650–1658.
Correspondence: Md. Zahidus Sayeed, MD, Cardiologist, Department of Cardiology Rajshahi Medical College Rajshahi-6000, Bangladesh Tel.:+8801718824627 fax: +880721772174 e-mail: [email protected]
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12578
Letter to the Editor
Extreme variability in clinical penetrance for a splice-site Plakophilin-2 mutation in a Bangladeshi family To the Editor: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/ARVD) is a relatively rare form of cardiomyopathy and a leading cause of sudden cardiac death in young adults (1). Mutations in the desmosomal genes are usually described, of which PKP2 mutation is the most prevalent with familial inheritance noted in about 50% of cases (2). At present, there is no definitive treatment for ARVC/ARVD but beta blockers are considered to have some efficacy to ameliorate the symptoms, and ICD implantation is recommended for secondary prevention (1). We first report a case of ARVC/ARVD from Bangladesh with its genotype and extended clinical and genetic surveillance among the family members. A 39-year-old male, elementary school teacher was admitted at Rajshahi Medical College Hospital, Bangladesh, with restlessness and panicky apprehended state in June 2012. He had recurrent palpitation with mild chest discomfort and a few episodes of dizziness followed by syncope. On examination, his blood pressure (BP) was 80/60 mmHg with rapid and thready pulse but lung bases were clear. Electrocardiogram (ECG) revealed a sustained monomorphic ventricular tachycardia (VT) of LBBB morphology with superiorly placed QRS axis (Fig. 1a,b). Initially, intravenous (IV) amiodarone failed to restore the sinus rhythm and eventually direct current (DC) cardioversion was needed. Sinus ECG revealed a typical epsilon wave in V1 with prolonged terminal activation duration along with T-wave inversion in the absence of RBBB in V1−V3 (Fig. 1c). On the following day, patient had multiple recurrences of monomorphic VT despite having adequate anti-ischemic and anti-arrhythmic medications that persisted for about 48 h when he finally became stabilized with either DC cardioversion and/or IV amiodarone. Coronary angiogram showed normal coronary arteries and no evidence of ischemia. Based on the revised task force criteria (epsilon wave, negative T wave in V1–V3, VT with LBBB morphology and superior axis), patient was clinically diagnosed as ARVC/ARVD. ICD implantation was advised, but patient declined because of financial incapacity. He was discharged with sotalol, 80 mg twice daily to be continued and periodic follow-up. Over 2 years follow-up, he was found reasonably well without any further recurrence of VT. But suddenly
502
he succumbed during sleep after 2.5 years of initial presentation. Analysis of desmosomal genes revealed a previously described (3) splice-site mutation 2490-1G > C, in the PKP2 gene, with a putative amino acid change of p.Asp829Glyfs2 (Fig. 1d). Mutation was also found in his youngest brother, but the father was negative. His mother, a 72-year-old asymptomatic lady was found positive for the mutation. Subsequent screening of the family members revealed additional five members positive for the mutation (two sisters, one maternal uncle, an aunt and one niece) (Fig. 1e). All mutation carriers (n = 7) were followed up for over a year through ECG, echocardiogram, exercise testing and 24-h ambulatory ECG monitoring. Male mutation carriers, i.e., proband’s youngest brother and second-degree maternal uncle complained a few episodes of palpitations, and their ECG showed early repolarization changes, but all females carriers were asymptomatic with normal ECGs. Cardiac MRI and SAECG could not be carried out due to lack of facility. The proband first expressed his phenotype at 39 years and died at 41 years, but his mother, through whom the mutation was transmitted, is still asymptomatic even at the age of 72 years. Such a long quiescent state can be explained with the non-penetrance phenotype of ARVC/ARVD in many cases, also family screening showed reduced penetrance and variable expressivity which are consistent with the natural course of PKP2 mutations (4). To our knowledge, this is the first genetic study of a family of ARVC/ARVCD with PKP2 mutation in Bangladesh where interesting genotype phenotype correlations are noted. This report indicates the presence of this rare arrhythmogenic cardiomyopathy in our population and demands further study to figure out its prevalence. Acknowledgement Dr. Z. A. B. is supported by a research grant from the Foundation Suisse de Cardiologie/number: 59283.
M.Z. Sayeeda M.A. Salamb A.K.M. Monwarul Islamc
Fig. 1. (a, b) Echocardiography (ECG) on admission showing VT with left bundle branch block (LBBB) morphology with superiorly placed QRS axis. (c) Arrowheads showing epsilon wave in lead V1 after direct-current (DC) cardioversion and prolonged terminal activation duration with T-wave inversion in right precordial leads without right bundle branch block (RBBB). (d) Splice acceptor site mutation in PKP2 gene in the intron 12 and exon 13 junctions. (e) Pedigree of the family with PKP2 mutation.
Letter to the Editor
503
Letter to the Editor Z.A. Bhuiyand of Cardiology, Rajshahi Medical College, Rajshahi 6000, Bangladesh b Department of Microbiology, Rajshahi Medical College, Rajshahi 6000, Bangladesh c Department of Cardiology, Jessore Medical College, Jessore, Bangladesh d Laboratoire de Diagnostic Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland a Department
References 1. Marcus FI, McKenna WJ, Sherrill D et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 2010: 121: 1533–1541.
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2. Kannankeril PJ, Bhuiyan ZA, Darbar D, Mannens MM, Wilde AA, Roden DM. Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: wide spectrum of disease in mutation carriers within a family. Heart Rhythm 2006: 3: 939–944. 3. Gerull B, Heuser A, Wichter T et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004: 36: 1162–1164. 4. Van Tintelen JP, Entius MM, Bhuiyan ZA et al. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation 2006: 113: 1650–1658.
Correspondence: Md. Zahidus Sayeed, MD, Cardiologist, Department of Cardiology Rajshahi Medical College Rajshahi-6000, Bangladesh Tel.:+8801718824627 fax: +880721772174 e-mail: [email protected]
