Brugada Syndrome

Clinical characteristics.

Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V₁-V₃ on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.

Diagnosis/testing.

Diagnosis is based on clinical findings and/or by the identification of a heterozygous (or hemizygous in the case of KCNE5 in a male) pathogenic variant in one of 23 genes: ABCC9, CACNA1C, CACNA2D1, CACNB2, FGF12, GPD1L, HCN4, KCND2, KCND3, KCNE5, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN5A, SCN10A, SEMA3A, SLMAP, and TRPM4.

Management.

Treatment of manifestations: Implantable cardioverter defibrillator (ICD) in individuals with a history of syncope or cardiac arrest; isoproterenol for electrical storms.

Prevention of primary manifestations: Quinidine (1-2 g daily). Treatment of asymptomatic individuals is controversial.

Prevention of secondary complication: During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by ECG.

Surveillance: ECG monitoring every one to two years for at-risk individuals with a family history of Brugada syndrome or who have a known pathogenic variant that can lead to Brugada syndrome.

Agents/circumstances to avoid: High fever, anesthetics, antidepressant drugs, and antipsychotic drugs with sodium-blocking effects; class 1 C antiarrhythmic drugs (i.e., flecainide, propafenone) and class 1A agents (i.e., procainamide, disopyramide).

Evaluation of relatives at risk: Identification of relatives at risk using ECG or (if the pathogenic variant in the family is known) molecular genetic testing enables use of preventive measures and avoidance of medications that can induce ventricular arrhythmias.

Genetic counseling.

In most cases Brugada syndrome is inherited in an autosomal dominant manner; the exception is KCNE5-related Brugada syndrome, which is inherited in an X-linked manner. Most individuals diagnosed with Brugada syndrome have an affected parent. The proportion of cases caused by a de novo pathogenic variant is estimated at 1%. Each child of an individual with autosomal dominant Brugada syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Suggestive Findings

Brugada syndrome should be suspected in individuals with any of the following findings:

• Recurrent syncope
• Ventricular fibrillation
• Self-terminating polymorphic ventricular tachycardia
• Cardiac arrest
• Family history of sudden cardiac death

AND one of the following ECG patterns:

• Type 1 ECG (elevation of the J wave ≥2 mm with a negative T wave and ST segment that is coved type and gradually descending) in more than one right precordial lead (V₁-V₃)* (see Figure 1) with or without administration of a sodium channel blocker (i.e., flecainide, pilsicainide, ajmaline, or procainamide)
  * No other factor(s) should account for the ECG abnormality.
• Type 2 ECG (elevation of the J wave ≥2 mm with a positive or biphasic T wave; ST segment with saddle-back configuration and elevated ≥1 mm) in more than one right precordial lead under baseline conditions with conversion to type 1 ECG following challenge with a sodium channel blocker
• Type 3 ECG (elevation of the J wave ≥2 mm with a positive T wave; ST segment with saddle-back configuration and elevated <1 mm) in more than one lead under baseline conditions with conversion to type 1 ECG following challenge with a sodium channel blocker

Figure 1.

Characteristic ECG in Brugada syndrome. Note presence of ST-segment elevation in leads V₁-V₃, coved type.

Establishing the Diagnosis

The diagnosis of Brugada syndrome is established in a proband with both of following findings and may include identification of a heterozygous (or hemizygous in the case of KCNE5 in a male) pathogenic variant in one of the genes listed in Tables 1a and 1b (see Note).

• Type 1 ECG (elevation of the J wave ≥2 mm with a negative T wave and ST segment that is coved type and gradually descending) in more than one right precordial lead (V₁-V₃)^* (see Figure 1) with or without administration of a sodium channel blocker (i.e., flecainide, pilsicainide, ajmaline, or procainamide)
  ^* No other factor(s) should account for the ECG abnormality.
• At least one of the following:
  • Documented ventricular fibrillation
  • Self-terminating polymorphic ventricular tachycardia
  • A family history of sudden cardiac death
  • Coved-type ECGs in family members
  • Electrophysiologic inducibility
  • Syncope or nocturnal agonal respiration

Note: In approximately 75% of persons affected by Brugada syndrome the diagnosis is established based on clinical history and ECG results. Molecular genetic testing confirms the diagnosis and may complement clinical testing [Benito et al 2009].

See Figure 2 for a diagnostic algorithm for Brugada syndrome.

Figure 2.

Diagnostic algorithm for Brugada syndrome From Berne & Brugada [2012]. Used by permission.

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Serial single-gene testing can be considered starting with SCN5A, heterozygous pathogenic variants in which account for 15%-30% of cases. Alternatively, serial single-gene testing may be considered if factors including clinical findings, laboratory findings, and ancestry indicate that mutation of a particular gene is most likely.
  Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes all current Brugada syndrome-related and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing and/or use of a multigene panel fails to confirm a diagnosis in an individual with features of Brugada syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

See Table 1a for the most common genetic causes (i.e., pathogenic variants of any one of the genes included in this table account for >1% of Brugada syndrome) and Table 1b for less common genetic causes (i.e., pathogenic variants of any one of the genes included in this table are reported in only a few families).

Clinical Description

Age at diagnosis. Brugada syndrome manifests primarily during adulthood, with a mean age of sudden death of approximately 40 years. The youngest individual diagnosed with the syndrome was two days old and the oldest age 85 years [Huang & Marcus 2004].

Gender differences. Although Brugada syndrome is more prevalent among males, it affects females as well, and both genders are at a high risk for ventricular arrhythmias and sudden death [Hong et al 2004b].

Presentation. Currently, the most common presentation is that of a person in his/her 40s with malignant arrhythmias and a previous history of syncopal episodes. Syncope is a common presenting symptom [Mills et al 2005, Benito & Brugada 2006, Karaca & Dinckal 2006].

Affected individuals in whom sustained ventricular arrhythmias are easily induced and who have a spontaneously abnormal ECG have a 45% likelihood of having an arrhythmic event at any time during life [Benito et al 2009]. Electrical storms (also known as arrhythmic storms), which are multiple episodes of ventricular arrhythmias that occur over a short period of time, are malignant but rare phenomena in Brugada syndrome. Incessant ventricular tachycardia (VT) is defined as hemodynamically stable VT continuing for hours.

Brugada syndrome can occur in conjunction with conduction disease. The presence of first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome in Brugada syndrome is not unusual [Smits et al 2005].

Clinical presentations of Brugada syndrome may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) [Priori et al 2000a, Antzelevitch 2001, Skinner et al 2005, Van Norstrand et al 2007] and sudden unexpected nocturnal death syndrome (SUNDS) [Vatta et al 2002], a syndrome seen in Southeast Asia in which young people die from cardiac arrest with no identifiable cause. The same pathogenic variant in SCN5A was identified in individuals with Brugada syndrome and SUNDS, thus supporting the hypothesis that they are the same disease [Hong et al 2004a].

Precipitating factors for the Brugada ECG pattern and the syndrome of sudden cardiac death (SCD) include fever, cocaine use, electrolyte disturbances, and use of class I antiarrhythmic medications and a number of other non-cardiac medications [Francis & Antzelevitch 2005]. Most importantly, in some (usually young) persons, the presence of the induced ECG pattern has been associated with sudden cardiac death. The pathophysiologic mechanisms behind this association remain largely unknown.

Predicting risk of malignant arrhythmias. Several parameters have been investigated to improve stratification of the risk of developing malignant arrhythmias (see Figure 3).

Figure 3.

Proposed risk stratification scheme and recommendations of ICD in individuals with Brugada syndrome From Berne & Brugada [2012]. Used by permission.

• Inducibility during electrophysiologic study (EPS) is the only parameter currently used for clinical decision making. During such a study the heart is electrically stimulated using intracardiac catheters. Although the inducibility of arrhythmias in an asymptomatic individual during the EPS is highly predictive of subsequent malignant events (arrhythmias and sudden cardiac death), the data remain controversial. Several groups do not use EPS for risk stratification in asymptomatic individuals; however, no other risk stratification parameter is presently available [Nunn et al 2010]. Thus, decisions regarding timing of implantation of a defibrillator vary widely among physicians and investigators [Eckardt et al 2005, Glatter et al 2005, Ikeda et al 2005, Al-Khatib 2006, Delise et al 2006, Gehi et al 2006, Imaki et al 2006, Ito et al 2006, Ott & Marcus 2006, Tatsumi et al 2006, Benito et al 2009].
• Genotype has been proposed as an additional parameter for risk stratification. Meregalli et al [2009] found that among individuals with an SCN5A pathogenic variant, those who were more symptomatic had more ECG signs of conduction slowing, supporting the notion that conduction slowing, mediated by loss-of-function SCN5A pathogenic variants, was a key pathophysiologic mechanism in Brugada syndrome. This limited study indicates that it may be possible in the future to use genotype information in risk stratification; however, at present this remains an area of investigation.

Pathophysiology. Brugada syndrome, caused by a sodium channelopathy, is associated with age-related progressive conduction abnormalities, such as prolongation of the ECG PQ, QRS, and HV intervals [Smits et al 2002, Yokokawa et al 2007]. Sodium current dysfunction contributes to local conduction block in the epicardium, resulting in multiple spikes within the QRS complex and triggering of atrial and ventricular fibrillation [Morita et al 2008].

Sodium channelopathies exhibited typical Brugada-type ECG and frequent arrhythmogenesis during bradycardia [Makiyama et al 2005]; both quinidine and isoproterenol normalized the J-ST elevation and prevented arrhythmias.

Genotype-Phenotype Correlations

Few studies have investigated genotype-phenotype correlations.

For SCN5A:

• The degree of ST elevation and the occurrence of arrhythmias were similar between persons with Brugada syndrome with and without a heterozygous SCN5A pathogenic variant [Morita et al 2009].
• In general the SCN5A pathogenic variants which cause LQT3 (see Long QT Syndrome) are associated with a gain of function rather than the loss of function associated with Brugada syndrome and progressive conduction system disease; however, pathogenic variants that are associated with both diseases in the same family have been described.
• By restoring (at least partially) sodium current defects, the common SCN5A variant p.His558Arg appears to modulate the phenotypic effects of heterozygous SCN5A pathogenic variants [Lizotte et al 2009] such as p.Thr512Ile, which results in clinically significant cardiac conduction disturbances [Viswanathan et al 2003], and p.Arg282His, which results in Brugada syndrome [Poelzing et al 2006].

Penetrance

Among individuals with an SCN5A pathogenic variant:

• Approximately 20%-30% have an ECG diagnostic of Brugada syndrome;
• Approximately 80% manifest the characteristic ECG changes when challenged with a sodium channel blocker (ajmaline) [Hong et al 2004b, Benito et al 2009].

Nomenclature

Vatta et al [2002] and Hong et al [2004a] determined that sudden unexpected nocturnal death syndrome (SUNDS) and Brugada syndrome are phenotypically, genetically, and functionally the same disorder. SUNDS was originally described in individuals from Southeast Asia. Other names for SUNDS include sudden and unexpected death syndrome (SUDS), bangungut (Philippines), non-lai tai (Laos), lai-tai (Thailand), and pokkuri (Japan).

Prevalence

Brugada syndrome was identified relatively recently; thus, it is difficult to determine its prevalence and population distribution. Further, because the ECG is dynamic and may normalize, diagnosis may be problematic, making it difficult to estimate the true incidence of Brugada syndrome in the general population.

Data suggest that Brugada syndrome occurs worldwide. The prevalence of the disease in endemic areas is on the order of 1:2,000 persons. In countries in Southeast Asia in which sudden unexpected nocturnal death syndrome (SUNDS) is endemic, it is the second cause (following accidents) of death of men under age 40 years.

Data from published studies indicate that Brugada syndrome is responsible for 4%-12% of unexpected sudden deaths and for up to 20% of all sudden death in individuals with an apparently normal heart.

As recognition of Brugada syndrome increases in the future, a sizeable increase in the number of identified cases can be expected.

A prospective study of an adult Japanese population (22,027 individuals) showed 12 individuals (prevalence of 0.05%) with ECGs compatible with Brugada syndrome [Tohyou et al 1995].

A second study of adults in Awa (Japan) showed a prevalence of 0.6% (66:10,420 individuals) [Namiki et al 1995].

In contrast, a third study in Japanese children showed only a 0.0006% (1:163,110) prevalence of ECGs compatible with Brugada syndrome [Hata et al 1997]. Therefore, in the absence of symptoms and/or molecular genetic testing of SCN5A, these studies provide an estimate of the prevalence of the Brugada syndrome ECG pattern (not of Brugada syndrome) in the population studied. The results suggest that Brugada syndrome manifests primarily during adulthood, a finding in concordance with the mean age of sudden death (age 35-40 years).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Brugada syndrome, the following evaluations are recommended:

• Electrocardiogram
• Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 ECG or type 3 ECG and suspicion of the disease
• Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals [Nunn et al 2010].
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Brugada syndrome is characterized by the presence of ST-segment elevation in leads V₁ to V₃. Implantable cardioverter defibrillators (ICDs) are the only therapy currently known to be effective in persons with Brugada syndrome with syncope or cardiac arrest [Brugada et al 1999, Wilde et al 2002]. See Figure 3 for risk stratification and recommendations of ICD in individuals with Brugada syndrome.

Electrical storms respond well to infusion of isoproterenol (1-3 µg/min), the first line of therapy before other antiarrhythmics [Maury et al 2004].

It is important to:

• Eliminate/treat agents/circumstances such as fever, cocaine use, electrolyte disturbances, and use of class I antiarrhythmic medications and other non-cardiac medications that can induce acute arrhythmias;
  AND
• Hospitalize the patient at least until the ECG pattern has normalized.

Controversy exists regarding the treatment of asymptomatic individuals. Recommendations vary [Benito et al 2009, Escárcega et al 2009, Nunn et al 2010] and include the following:

• Observation until the first symptom develops (the first symptom can also be sudden cardiac death)
• Placement of an ICD if the family history is positive for sudden cardiac death
• Use of electrophysiologic study (EPS) to identify those most likely to experience arrhythmias and thus to benefit the most from placement of an ICD

Prevention of Primary Manifestations

Quinidine (1-2 g daily) has been shown to restore ST segment elevation and decrease the incidence of arrhythmias [Belhassen et al 2004, Hermida et al 2004, Probst et al 2006].

Prevention of Secondary Complications

During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by ECG.

Surveillance

At-risk individuals with a family history of Brugada syndrome or a known pathogenic variant should undergo ECG monitoring every one to two years beginning at birth [Oe et al 2005]. The presence of type I ECG changes should be further investigated.

Agents/Circumstances to Avoid

The following can unmask the Brugada syndrome ECG [Antzelevitch et al 2002]:

• Febrile state
• Vagotonic agents
• α-adrenergic agonists [Miyazaki et al 1996]
• β-adrenergic antagonists
• Tricyclic antidepressants
• First-generation antihistamines (dimenhydrinate)
• Cocaine toxicity

The following should be avoided [Antzelevitch et al 2003]:

• Class 1C antiarrhythmic drugs including flecainide and propafenone
• Class 1A agents including procainamide and disopyramide

Evaluation of Relatives at Risk

If the pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk relatives is appropriate because:

• ECG changes have low sensitivity in establishing the diagnosis [Priori et al 2003];
• Identification of individuals at risk allows preventive measures such as avoidance of medications that can induce ventricular arrhythmias;
• Surveillance can then be limited to family members who have the identified pathogenic variant [Benito et al 2009, Escárcega et al 2009, Nunn et al 2010].

If the pathogenic variant has not been identified in the family, relatives should be screened with an ECG. If a type I ECG is identified, further investigation is warranted.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Hormonal changes during pregnancy can precipitate arrhythmic events in women with Brugada syndrome. Recurrent ventricular tachyarrhythmia can be inhibited and the electrocardiographic pattern can normalize following IV infusion of low-dose isoproterenol followed by oral quinidine [Sharif-Kazemi et al 2011].

Quinidine is not known to be teratogenic to the developing fetus and is a preferred drug to treat arrhythmia in pregnancy. See www.mothertobaby.org for more information about medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.