EDITORIAL COMMENTARY
Double trouble, stick to the basics should be the rule! Arthur A.M. Wilde, MD, PhD,*† Krystien V.V. Lieve, MD* From the *Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands. and † Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. Inherited arrhythmia syndromes are, in general, considered to be rare. Indeed, its prevalence is between 1:2000 (long QT syndrome [LQTS]) and 1:10,000 (catecholaminergic polymorphic ventricular tachycardia [CPVT]).1 All these diseases associate with sudden cardiac death at young age, and it is therefore important that they (ie, “the red flags”) are timely recognized and treated. Both diagnosis and management may be guided by the recent consensus document endorsed by the 3 main electrophysiological societies worldwide.1 In the diagnostic workup of the proband (ie, the first individual within a family providing evidence for one of the diseases), history taking and clinical testing is most important, and particular interest should be targeted to existing disease-specific features. Ultimately, this may be supplemented by genetic testing, which may become increasingly important, however. In this issue of HeartRhythm, Janson et al2 present a case of a 7-year-old boy who was presented for evaluation after syncopal events during swimming and exercise. The first electrocardiogram (ECG), echocardiogram, and Holter testing were unremarkable. However, the second and third ECGs showed abnormalities that were strongly suggestive of Brugada syndrome (BrS). With this as the working diagnosis, an implantable cardioveter-defibrillator was implanted. Genetic testing directed toward BrS was negative (7 genes tested). In the year after implantation, he suffered from 8 appropriate shocks for episodes of exertion-related ventricular tachycardia that degenerated into ventricular fibrillation. A subsequently performed exercise test was, with an apparent (short) bidirectional ventricular tachycardia (Figure 3 of their article), diagnostic of CPVT.1 Genetic testing revealed a putative (de novo) pathogenic ryanodine receptor 2 variant.2 On retrospect, clearly, the exercise test should have been performed in the initial workup. Indeed, exercise-related and The authors acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences. Address reprint requests and correspondence: Dr Arthur A. M. Wilde, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
swimming-related events are typical of CPVT and LQTS (type 1, in particular),3,4 but the latter is unlikely (but not excluded) with a completely normal baseline ECG. To the contrary, exertion-related events are atypical of BrS, although exercise-related augmentation of right precordial ST-segment elevation has been described.5 Hence, an important lesson to learn is that whenever history taking does not match a putative clinical diagnosis, additional investigation is warranted. In other words, stick to the basics when it comes to diagnostic workup. This unfortunate case is an example of 2 different diseases in the same patient. Based on the prevalence of the 2 diseases (CPVT and BrS), it is expected to be rare (1 in 2000 10,000 ¼ 2 107 in this case). The presence of 2 different diseases, that is, “double trouble,” in the same patient/family, however, has been described before. Beckmann et al6 described a family with both CPVT and LQTS1. This family was examined because of recurrent sudden death in several young family members. A borderline prolonged corrected QT interval was noted in an asymptomatic individual and subsequent genetic analysis revealed a nonsense KCNQ1 mutation. Cascade screening was initiated in all consenting family members, and individuals not carrying the KCNQ1 variant were reassured. Unfortunately, however, shortly after, a young girl died suddenly. Furthermore, several other family members had symptoms such as syncope in the setting of a completely normal baseline electrocardiogram. Subsequent exercise testing revealed exercise-induced ventricular arrhythmias typical of CPVT. Indeed, genetic analysis revealed an additional RYR2 mutation cosegregating in this family. Hence, here there was a mismatch between the clinical history and the genetic diagnosis, and that also includes the relatively benign aspect of nonsense KCNQ1 mutations and the malignant family history.7 More frequently, 2 apparent different diseases in the same patient/family are caused by single mutations. In particular, SCN5A mutations are prone to this. The “classical” example is the 1795insD mutations in a large Dutch family presenting with a combination of loss-of-function phenotype (BrS, conduction disease at different cardiac levels) and a gainof-function phenotype (LQTS type 3).8 Many more examples with different combinations have been described.9
http://dx.doi.org/10.1016/j.hrthm.2014.07.026
2 “Double trouble” may also be caused by “double hits” within genes related to a single disease entity. In LQTS, double hits come in different flavors; they are rare but not uncommon. Homozygosity for KCNQ1 or KCNE1 variants is well known and usually associates with congenital sensoneuronal deafness (Jervell and Lange-Nielsen syndrome). Homozygous mutations in KCNH2 have also been described.10 Alternatively, 2 different mutations in the same gene encoding the same disease (compound heterozygosity) or 2 mutations in 2 separate genes encoding the same disease (digenic heterozygosity) may be observed. Actually, in LQTS, compound mutations are indeed not rare and have an estimated prevalence of ⫾7%–9% in non-research–based cohorts sent for genetic testing.11,12 Not surprisingly, these double hits lead to more severe phenotypes,13 which has also been described in, for example, hypertrophic cardiomyopathy.14 The identification of the correct clinical diagnosis is clearly of great importance. In the case described by Janson et al,2 implantable cardioveter-defibrillator implantation could possibly have been avoided. The patient was free of events after receiving a β-blocker. Follow-up duration, however, is not given, and no follow-up exercise tests are reported. Hence, it is not known whether the patient is sufficiently protected only by a β-blocker. The addition of flecainide, quite effective in the vast majority of patients affected with CPVT,15 is precluded in this patient because of the coexistence of BrS. In the family reported by Beckmann et al,6 additional deaths could probably have been avoided by a timely fully correct diagnosis. In conclusion, rare arrhythmia syndromes may occasionally cosegregate. A mismatch between anamnestic details (reported by the patient or known from his or her family history) and initial clinical results with the apparent diagnosis should alert the treating physician for “double trouble.” Further clinical testing is then warranted and genetic testing maybe helpful, although in many cases it will not provide the
Heart Rhythm, Vol 0, No 0, Month 2014 definite diagnosis. In any case, “stick to the basics” should be leading.
References 1. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:1932–1963. 2. Janson CM, Ceresnak SR, Chung WK, Pass RH. Catecholaminergic polymorphic ventricular tachycardia in a child with Brugada pattern on ECG: one patient with two diseases? Heart Rhythm 2014;XX:XX–XXX. 3. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89–95. 4. Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman MJ. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004;110:2119–2124. 5. Amin AS, de Groot EAA, Ruijter JM, Wilde AAM, Tan HL. Exercise-induced ECG changes in Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2: 531–539. 6. Beckmann BM, Wilde AAM, Kääb S. Dual inheritance of sudden death from cardiovascular causes. N Engl J Med 2008;358:2077–2078. 7. Moss AJ, Shimizu W, Wilde AAM, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007;115:2481–2489. 8. Bezzina C, Veldkamp MW, van Den Berg MP, et al. A single Na(þ) channel mutation causing both long-QT and Brugada syndromes. Circ Res 1999;85: 1206–1213. 9. Remme CA, Bezzina CR. Sodium channel (dys)function and cardiac arrhythmias. Cardiovasc Ther 2010;28:287–294. 10. Bhuiyan ZA, Momenah TS, Gong Q, et al. Recurrent intrauterine fetal loss due to near absence of HERG: clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation. Heart Rhythm 2008;5:553–561. 11. Lieve KV, Williams L, Daly A, et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers 2013;17:553–561. 12. Kapplinger JD, Tester DJ, Salisbury BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm 2009;6:1297–1303. 13. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation 2004;109:1834–1841. 14. Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44:1903–1910. 15. Van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244–2254.
Double trouble, stick to the basics should be the rule! Arthur A.M. Wilde, MD, PhD,*† Krystien V.V. Lieve, MD* From the *Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands. and † Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. Inherited arrhythmia syndromes are, in general, considered to be rare. Indeed, its prevalence is between 1:2000 (long QT syndrome [LQTS]) and 1:10,000 (catecholaminergic polymorphic ventricular tachycardia [CPVT]).1 All these diseases associate with sudden cardiac death at young age, and it is therefore important that they (ie, “the red flags”) are timely recognized and treated. Both diagnosis and management may be guided by the recent consensus document endorsed by the 3 main electrophysiological societies worldwide.1 In the diagnostic workup of the proband (ie, the first individual within a family providing evidence for one of the diseases), history taking and clinical testing is most important, and particular interest should be targeted to existing disease-specific features. Ultimately, this may be supplemented by genetic testing, which may become increasingly important, however. In this issue of HeartRhythm, Janson et al2 present a case of a 7-year-old boy who was presented for evaluation after syncopal events during swimming and exercise. The first electrocardiogram (ECG), echocardiogram, and Holter testing were unremarkable. However, the second and third ECGs showed abnormalities that were strongly suggestive of Brugada syndrome (BrS). With this as the working diagnosis, an implantable cardioveter-defibrillator was implanted. Genetic testing directed toward BrS was negative (7 genes tested). In the year after implantation, he suffered from 8 appropriate shocks for episodes of exertion-related ventricular tachycardia that degenerated into ventricular fibrillation. A subsequently performed exercise test was, with an apparent (short) bidirectional ventricular tachycardia (Figure 3 of their article), diagnostic of CPVT.1 Genetic testing revealed a putative (de novo) pathogenic ryanodine receptor 2 variant.2 On retrospect, clearly, the exercise test should have been performed in the initial workup. Indeed, exercise-related and The authors acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences. Address reprint requests and correspondence: Dr Arthur A. M. Wilde, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, Amsterdam, The Netherlands. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
swimming-related events are typical of CPVT and LQTS (type 1, in particular),3,4 but the latter is unlikely (but not excluded) with a completely normal baseline ECG. To the contrary, exertion-related events are atypical of BrS, although exercise-related augmentation of right precordial ST-segment elevation has been described.5 Hence, an important lesson to learn is that whenever history taking does not match a putative clinical diagnosis, additional investigation is warranted. In other words, stick to the basics when it comes to diagnostic workup. This unfortunate case is an example of 2 different diseases in the same patient. Based on the prevalence of the 2 diseases (CPVT and BrS), it is expected to be rare (1 in 2000 10,000 ¼ 2 107 in this case). The presence of 2 different diseases, that is, “double trouble,” in the same patient/family, however, has been described before. Beckmann et al6 described a family with both CPVT and LQTS1. This family was examined because of recurrent sudden death in several young family members. A borderline prolonged corrected QT interval was noted in an asymptomatic individual and subsequent genetic analysis revealed a nonsense KCNQ1 mutation. Cascade screening was initiated in all consenting family members, and individuals not carrying the KCNQ1 variant were reassured. Unfortunately, however, shortly after, a young girl died suddenly. Furthermore, several other family members had symptoms such as syncope in the setting of a completely normal baseline electrocardiogram. Subsequent exercise testing revealed exercise-induced ventricular arrhythmias typical of CPVT. Indeed, genetic analysis revealed an additional RYR2 mutation cosegregating in this family. Hence, here there was a mismatch between the clinical history and the genetic diagnosis, and that also includes the relatively benign aspect of nonsense KCNQ1 mutations and the malignant family history.7 More frequently, 2 apparent different diseases in the same patient/family are caused by single mutations. In particular, SCN5A mutations are prone to this. The “classical” example is the 1795insD mutations in a large Dutch family presenting with a combination of loss-of-function phenotype (BrS, conduction disease at different cardiac levels) and a gainof-function phenotype (LQTS type 3).8 Many more examples with different combinations have been described.9
http://dx.doi.org/10.1016/j.hrthm.2014.07.026
2 “Double trouble” may also be caused by “double hits” within genes related to a single disease entity. In LQTS, double hits come in different flavors; they are rare but not uncommon. Homozygosity for KCNQ1 or KCNE1 variants is well known and usually associates with congenital sensoneuronal deafness (Jervell and Lange-Nielsen syndrome). Homozygous mutations in KCNH2 have also been described.10 Alternatively, 2 different mutations in the same gene encoding the same disease (compound heterozygosity) or 2 mutations in 2 separate genes encoding the same disease (digenic heterozygosity) may be observed. Actually, in LQTS, compound mutations are indeed not rare and have an estimated prevalence of ⫾7%–9% in non-research–based cohorts sent for genetic testing.11,12 Not surprisingly, these double hits lead to more severe phenotypes,13 which has also been described in, for example, hypertrophic cardiomyopathy.14 The identification of the correct clinical diagnosis is clearly of great importance. In the case described by Janson et al,2 implantable cardioveter-defibrillator implantation could possibly have been avoided. The patient was free of events after receiving a β-blocker. Follow-up duration, however, is not given, and no follow-up exercise tests are reported. Hence, it is not known whether the patient is sufficiently protected only by a β-blocker. The addition of flecainide, quite effective in the vast majority of patients affected with CPVT,15 is precluded in this patient because of the coexistence of BrS. In the family reported by Beckmann et al,6 additional deaths could probably have been avoided by a timely fully correct diagnosis. In conclusion, rare arrhythmia syndromes may occasionally cosegregate. A mismatch between anamnestic details (reported by the patient or known from his or her family history) and initial clinical results with the apparent diagnosis should alert the treating physician for “double trouble.” Further clinical testing is then warranted and genetic testing maybe helpful, although in many cases it will not provide the
Heart Rhythm, Vol 0, No 0, Month 2014 definite diagnosis. In any case, “stick to the basics” should be leading.
References 1. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:1932–1963. 2. Janson CM, Ceresnak SR, Chung WK, Pass RH. Catecholaminergic polymorphic ventricular tachycardia in a child with Brugada pattern on ECG: one patient with two diseases? Heart Rhythm 2014;XX:XX–XXX. 3. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89–95. 4. Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman MJ. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004;110:2119–2124. 5. Amin AS, de Groot EAA, Ruijter JM, Wilde AAM, Tan HL. Exercise-induced ECG changes in Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2: 531–539. 6. Beckmann BM, Wilde AAM, Kääb S. Dual inheritance of sudden death from cardiovascular causes. N Engl J Med 2008;358:2077–2078. 7. Moss AJ, Shimizu W, Wilde AAM, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007;115:2481–2489. 8. Bezzina C, Veldkamp MW, van Den Berg MP, et al. A single Na(þ) channel mutation causing both long-QT and Brugada syndromes. Circ Res 1999;85: 1206–1213. 9. Remme CA, Bezzina CR. Sodium channel (dys)function and cardiac arrhythmias. Cardiovasc Ther 2010;28:287–294. 10. Bhuiyan ZA, Momenah TS, Gong Q, et al. Recurrent intrauterine fetal loss due to near absence of HERG: clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation. Heart Rhythm 2008;5:553–561. 11. Lieve KV, Williams L, Daly A, et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers 2013;17:553–561. 12. Kapplinger JD, Tester DJ, Salisbury BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm 2009;6:1297–1303. 13. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation 2004;109:1834–1841. 14. Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44:1903–1910. 15. Van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244–2254.
