A variant of Brugada syndrome Maryna Popp Switzer, DO, Mohamed Teleb, MD, Enoch Agunanne, MD, and Aamer Abbas, MD
Brugada syndrome is an inherited disorder that can present with syncope, cardiac arrest, or sudden cardiac death. Multiple genetic mutations have been described that cause this disease. We present a 56-year-old man who sustained an out-of-hospital cardiac arrest, was resuscitated, and was found to have typical features of the Brugada criteria on the electrocardiogram. Genetic testing was positive for a heterozygous mutation in the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene with a p. Leu227Pro (L227P) variant located on exon 6. To our knowledge, this is the first described case with this variant causing malignant arrhythmia with a cardiac arrest. Figure 1. Initial ECG showing first-degree atrioventricular block with mild elevation of the ST segment in V2.
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escribed initially in 1992, Brugada syndrome has an incidence of 0.05% to 0.60% (1, 2). Occurring most frequently in Asians, it is also observed in Caucasians, African Americans, and Hispanics. The syndrome is characterized by typical electrocardiogram characteristics consisting of right bundle branch block and ST segment elevations in leads V1 to V3. Brugada syndrome is inherited in an autosomal dominant pattern. Multiple genetic mutations have been described. CASE PRESENTATION A 56-year-old man sustained an out-of-hospital cardiac arrest. Shortly after he went to bed, his wife noticed he was having labored respirations. Since the family could not wake him, they initiated cardiopulmonary resuscitation and called emergency medical services. The patient was found to be in ventricular fibrillation; he was cardioverted and transferred to the University Medical Center with cardiopulmonary resuscitation in progress. On arrival, he was resuscitated, intubated, and mechanically ventilated. He was transferred to the medical intensive care unit, and a hypothermia protocol was initiated. Prior to this event, the patient did not have any syncope or presyncopal episodes and was not taking any medications. He was adopted and did not know any medical history from his father’s side. The first electrocardiogram (ECG) obtained following resuscitation demonstrated first-degree atrioventricular block with suspicious coving of the ST segment in lead V2 (Figure 1). Left heart catheterization revealed no evidence of coronary heart disease. Cardiac magnetic resonance imaging was negative for 62
contractile abnormalities of the left ventricle, and there was no evidence of noncompacted myocardium or trabeculation. A repeat ECG was obtained during the hospitalization revealing coving of the ST segment in V1 and V2 consistent with the Brugada criteria (Figure 2). The patient made an excellent recovery with a return to normal neurological function. An implantable cardioverter defibrillator was placed prior to his discharge from the hospital. When genetic testing was obtained, a heterozygous mutation was found in the SCN5A gene with a L227P variant located on exon 6. DISCUSSION The Brugada syndrome is an inherited arrhythmogenic disorder. Individuals with Brugada syndrome are at a higher risk of arrhythmia, such as ventricular tachycardia or ventricular fibrillation, and of sudden cardiac death. The average age of presentation is 41 ± 15 years (3). Men are much more frequently affected than women, with a 9:1 ratio. Men are also more likely to be symptomatic, presenting with cardiac events such as syncope or cardiac arrest, and generally tend to have a worse prognosis (1, 4). From the Departments of Internal Medicine (Switzer, Teleb, Agunanne, Abbas) and Cardiology (Teleb, Agunanne, Abbas), Texas Tech University Health Sciences Center, El Paso, Texas. Corresponding author: Mohamed Teleb, MD, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2017;30(1):62–63
Figure 2. A repeat ECG showing coving of the ST segment in V1 to V2, consistent with Brugada criteria.
To diagnose Brugada syndrome, typical ECG findings need to be present, along with one of the following: a personal history of ventricular tachycardia or ventricular fibrillation, the presence of ventricular tachycardia or ventricular fibrillation during an electrophysiological study, a family history of sudden cardiac death or a coved-type ECG, or agonal breathing during sleep. Three types of ECG abnormalities have been described: • Type 1 consists of coved-type ST segment elevation of ≥2 mm followed by a negative T wave. • Type 2 is a saddle-back–type ST segment elevation of ≥2 mm that gradually decreases and is followed by a positive or biphasic T wave. • Type 3 is an ST segment elevation 200 control subjects, wild-type (WT) SCN10A with WT-SCN5A in human embryonic kidney cells caused more arrhythmia effect, including PR interval prolongation (2). Since the discovery of Brugada syndrome, SCN5A has represented about 15% to 30% of all diagnosed cases, making it the most common genotype. A loss of function mutation of SCN5A leads to reduced sodium current available for exchange with the plasma membrane or actual alternation in channel properties. On the other hand, a gain of function leads to arrhythmia syndromes such as prolonged QT. It is important to recognize that since 2004, more genetics analysis research has discovered the presence of rare mis-
January 2017
sense SCN5A variants in 2% of healthy white subjects and 5% of healthy nonwhite subjects. This discovery is important for differentiating between the rare harmless mutations and the pathological ones. Multinational analysis evaluated 2111 patients referred for genetic testing for possible diagnosis of Brugada syndrome and involved 27 translated exons present in the SCN5A gene. The statistical analysis revealed four common mutations—E1784K, F861WfsX90, D356N, and G1408R— most of which were found to be missense mutations, with the rest involving radical mutations such as frame shift. Eighteen patients had mutations on exon 6, of which 13 were missense mutations, 4 nonsense, and 1 frame shift; none had the L227P variant (8). It is important to evaluate more variants to identify the pathological ones requiring early screening to prevent complications. As reported in our patient, the heterozygous mutation in the SCN5A gene with the L227P variant located on exon 6 seems to be the first reported in the literature causing arrhythmia and cardiac arrest. 1. 2.
3. 4.
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Sheikh AS, Ranjan K. Brugada syndrome: a review of the literature. Clin Med (Lond) 2014;14(5):482–489. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20(6): 1391–1396. Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5(3):606–616. Benito B, Sarkozy A, Mont L, Henkens S, Berruezo A, Tamborero D, Arzamendi D, Berne P, Brugada R, Brugada P, Brugada J. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol 2008;52(19):1567–1573. Hu D, Barajas-Martínez H, Pfeiffer R, Buch T, Betzenhauser MJ, Belardinelli L, Kahlig KM, Rajamani S, DeAntonio HJ, Myerburg RJ, Ito H, Deshmukh P, Marieb M, Nam GB, Bhatia A, Hasdemir C, Haïssaguerre M, Veltmann C, Schimpf R, Borggrefe M, Viskin S, Antzelevitch C. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J Am Coll Cardiol 2014;64(1):66–79. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014;133(1):1–9. Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, Keating MT, Jones G, Chadha M, Burrow CR, Stephens JC, Xu C, Judson R, Curran ME. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 2004;1(5):600–607. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7(1):33–46.
A variant of Brugada syndrome
63
Brugada syndrome is an inherited disorder that can present with syncope, cardiac arrest, or sudden cardiac death. Multiple genetic mutations have been described that cause this disease. We present a 56-year-old man who sustained an out-of-hospital cardiac arrest, was resuscitated, and was found to have typical features of the Brugada criteria on the electrocardiogram. Genetic testing was positive for a heterozygous mutation in the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene with a p. Leu227Pro (L227P) variant located on exon 6. To our knowledge, this is the first described case with this variant causing malignant arrhythmia with a cardiac arrest. Figure 1. Initial ECG showing first-degree atrioventricular block with mild elevation of the ST segment in V2.
D
escribed initially in 1992, Brugada syndrome has an incidence of 0.05% to 0.60% (1, 2). Occurring most frequently in Asians, it is also observed in Caucasians, African Americans, and Hispanics. The syndrome is characterized by typical electrocardiogram characteristics consisting of right bundle branch block and ST segment elevations in leads V1 to V3. Brugada syndrome is inherited in an autosomal dominant pattern. Multiple genetic mutations have been described. CASE PRESENTATION A 56-year-old man sustained an out-of-hospital cardiac arrest. Shortly after he went to bed, his wife noticed he was having labored respirations. Since the family could not wake him, they initiated cardiopulmonary resuscitation and called emergency medical services. The patient was found to be in ventricular fibrillation; he was cardioverted and transferred to the University Medical Center with cardiopulmonary resuscitation in progress. On arrival, he was resuscitated, intubated, and mechanically ventilated. He was transferred to the medical intensive care unit, and a hypothermia protocol was initiated. Prior to this event, the patient did not have any syncope or presyncopal episodes and was not taking any medications. He was adopted and did not know any medical history from his father’s side. The first electrocardiogram (ECG) obtained following resuscitation demonstrated first-degree atrioventricular block with suspicious coving of the ST segment in lead V2 (Figure 1). Left heart catheterization revealed no evidence of coronary heart disease. Cardiac magnetic resonance imaging was negative for 62
contractile abnormalities of the left ventricle, and there was no evidence of noncompacted myocardium or trabeculation. A repeat ECG was obtained during the hospitalization revealing coving of the ST segment in V1 and V2 consistent with the Brugada criteria (Figure 2). The patient made an excellent recovery with a return to normal neurological function. An implantable cardioverter defibrillator was placed prior to his discharge from the hospital. When genetic testing was obtained, a heterozygous mutation was found in the SCN5A gene with a L227P variant located on exon 6. DISCUSSION The Brugada syndrome is an inherited arrhythmogenic disorder. Individuals with Brugada syndrome are at a higher risk of arrhythmia, such as ventricular tachycardia or ventricular fibrillation, and of sudden cardiac death. The average age of presentation is 41 ± 15 years (3). Men are much more frequently affected than women, with a 9:1 ratio. Men are also more likely to be symptomatic, presenting with cardiac events such as syncope or cardiac arrest, and generally tend to have a worse prognosis (1, 4). From the Departments of Internal Medicine (Switzer, Teleb, Agunanne, Abbas) and Cardiology (Teleb, Agunanne, Abbas), Texas Tech University Health Sciences Center, El Paso, Texas. Corresponding author: Mohamed Teleb, MD, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2017;30(1):62–63
Figure 2. A repeat ECG showing coving of the ST segment in V1 to V2, consistent with Brugada criteria.
To diagnose Brugada syndrome, typical ECG findings need to be present, along with one of the following: a personal history of ventricular tachycardia or ventricular fibrillation, the presence of ventricular tachycardia or ventricular fibrillation during an electrophysiological study, a family history of sudden cardiac death or a coved-type ECG, or agonal breathing during sleep. Three types of ECG abnormalities have been described: • Type 1 consists of coved-type ST segment elevation of ≥2 mm followed by a negative T wave. • Type 2 is a saddle-back–type ST segment elevation of ≥2 mm that gradually decreases and is followed by a positive or biphasic T wave. • Type 3 is an ST segment elevation 200 control subjects, wild-type (WT) SCN10A with WT-SCN5A in human embryonic kidney cells caused more arrhythmia effect, including PR interval prolongation (2). Since the discovery of Brugada syndrome, SCN5A has represented about 15% to 30% of all diagnosed cases, making it the most common genotype. A loss of function mutation of SCN5A leads to reduced sodium current available for exchange with the plasma membrane or actual alternation in channel properties. On the other hand, a gain of function leads to arrhythmia syndromes such as prolonged QT. It is important to recognize that since 2004, more genetics analysis research has discovered the presence of rare mis-
January 2017
sense SCN5A variants in 2% of healthy white subjects and 5% of healthy nonwhite subjects. This discovery is important for differentiating between the rare harmless mutations and the pathological ones. Multinational analysis evaluated 2111 patients referred for genetic testing for possible diagnosis of Brugada syndrome and involved 27 translated exons present in the SCN5A gene. The statistical analysis revealed four common mutations—E1784K, F861WfsX90, D356N, and G1408R— most of which were found to be missense mutations, with the rest involving radical mutations such as frame shift. Eighteen patients had mutations on exon 6, of which 13 were missense mutations, 4 nonsense, and 1 frame shift; none had the L227P variant (8). It is important to evaluate more variants to identify the pathological ones requiring early screening to prevent complications. As reported in our patient, the heterozygous mutation in the SCN5A gene with the L227P variant located on exon 6 seems to be the first reported in the literature causing arrhythmia and cardiac arrest. 1. 2.
3. 4.
5.
6.
7.
8.
Sheikh AS, Ranjan K. Brugada syndrome: a review of the literature. Clin Med (Lond) 2014;14(5):482–489. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20(6): 1391–1396. Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5(3):606–616. Benito B, Sarkozy A, Mont L, Henkens S, Berruezo A, Tamborero D, Arzamendi D, Berne P, Brugada R, Brugada P, Brugada J. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol 2008;52(19):1567–1573. Hu D, Barajas-Martínez H, Pfeiffer R, Buch T, Betzenhauser MJ, Belardinelli L, Kahlig KM, Rajamani S, DeAntonio HJ, Myerburg RJ, Ito H, Deshmukh P, Marieb M, Nam GB, Bhatia A, Hasdemir C, Haïssaguerre M, Veltmann C, Schimpf R, Borggrefe M, Viskin S, Antzelevitch C. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J Am Coll Cardiol 2014;64(1):66–79. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014;133(1):1–9. Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, Keating MT, Jones G, Chadha M, Burrow CR, Stephens JC, Xu C, Judson R, Curran ME. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 2004;1(5):600–607. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7(1):33–46.
A variant of Brugada syndrome
63
