|Year : 2015 | Volume
| Issue : 2 | Page : 112-117
Genetic and clinical aspects of brugada syndrome
Laila Anjuman Banu1, Rifat Ara Najnin2
1 Department of Genetic and Molecular Biology, Faculty of Basic Medical and Paraclinical Sciences, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
2 Scientific Officer, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
|Date of Web Publication||5-Jul-2017|
Laila Anjuman Banu
Departyment of Genetic and Molecular Biology, Faculty of Basic Medical and Paraclinical Sciences, Bangabandhu Sheikh Mujib Medical University(BSMMU)
Source of Support: None, Conflict of Interest: None
Death is always dreadful and the diseases those causes sudden death are universal threats in health concern. Brugada syndrom is a recently identified entity of arrhythmia and sudden cardiac death. This genetic and male dominant disorder is prevalent in Southeast Asian region. At least seven genes have been identified to associate with its occurrence though the detail pathophysiological mechanism is till to be resolved. The correlation of ion channel genes to Brugada syndrom is still dubious as the same genes also related to other cardiac diseases. Here we review the genetic aspects of Brugada syndrom with a breif overview of epidemiology, diagnosis and management system.
Keywords: Brugada sydrome, Ventricular fibrillation, Sudden cardiac death, Channelopathy genes, Coved type ECG
|How to cite this article:|
Banu LA, Najnin RA. Genetic and clinical aspects of brugada syndrome. Acta Med Int 2015;2:112-7
| Introduction|| |
Brugada syndrome, a newly discovered medical phenomena, known as sudden unexpected nocturnal death syndrome or sudden unexplained death syndrome which characterized by ventricular arrhythmia, ST segment elevation and syncope.
There is an interesting story about the disease among the indigenous population of Thailand. The sudden death of young male at night gives the topic an enigmatic smell that widow ghost came to take them away at night. Many young men actually dress still as women to go to sleep at night - a practice carried out for more than 70 years - with the hope that it would deceive the widow ghost, who then would not take these young men.There are some local name of this disease; for example, in Philippines the phenomenon was known as Bangungut (scream followed by sudden death during sleep) and in Japan as Pokkuri (unexpected sudden death at night).
The disease primarily exhibit during adulthood and 40 years is the mean age of affected person. However, the youngest individual diagnosed with the syndrome was two days old and the oldest age 85 years.
Though the detail pathophysiological mechanism is vague, association of genetic factor with Brugada syndrome is already reported where the mutation in the ion channel proteins causes the disruption of the function of channel during action potential. This is a male predominant disorder, transmitted as autosomal dominant and incomplete penetrance mode. In recent years the high incidence of Brugada syndrome prompted scientist to extensively investigate about this disease as this is recognized as a motive of sudden cardiac death in young men, especially in Southeast Asia. In this study we want to review the genetic association of Brugada syndrome to ion channel genes with an overview of epidemiology, diagnosis, causal factors and probable management system of this disease.
The term “Brugada syndrome” was first introduced by Pedro and Josep Brugada in 1992. In East/Southeast Asia, the occurrence rate of this disease is higher than other area particularly prevalent in Japan and Thailand while in China and Korea the reported frequency is lower. In Thai population the prevalence rate is 2–38 per 100 000 population. In a study of Japanese population, the reported prevalence of type-1 ECG pattern to be 12/10000.
Asian population have a prevalence of occuring Brugada syndrome and higher muatation rate in SCN5A gene might be an explanation for this event. This fact is supported by an experiment performed by Bezzina and co-workers where interesting evidence corroborate the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction. The occurrence rate is more tremendous in Europe than America. In overall analysis although this clinical syndrome is considered as a rare entity throughout the world with an estimated prevalence of 5–50 cases per 10,000, the severity and unexpected death rate make the topic discussable.
The first experimental event of Brugada syndrome in Bangladesh is a 55 year old farmer, initially studied by M. Zahidus Sayeed et al with type-1 brugada ECG pattern. This is a case of sporadic mutation in SCN5A gene without any genetic prehistory though the person has transmitted the mutation into one of his offspring.
The observed frequency of Brugada syndrome is 10 times more in male than female, an atypical phenomena of autosomaly inherited disorder, as genotype is transmitted in equal proportion to males and female. An explanation for this biased prevalence towards male may be a result of the presence of a more prominent Ito and IL,Ca channels in males than female. Some researcher also suspect that testosterone, a sex hormone present at much higher levels in men, may be responsible for this difference.
The characteristic clinical signs of Brugada syndrome are ventricular fibrillation or aborted sudden cardiac death, syncope, nocturnal agonal respiration, palpitations, and chest discomfort. These symptoms are documented frequently at rest, during sleep, or under other vagotonic conditions, rarely during exercise. 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, where syncope is the most common feature of this disease. Generally Structural abnormality in heart is not observed in Brugada syndrome.
| Genetic Aspects of Brugada Syndrome|| |
Brugada Syndrome and Mutations in Sodium Channel GSSenes
Mutation in SCN5A gene
Genetic association of Brugada syndrome has been identified by mutation in the SCN5A gene,on chromosome 3p21 contains 28 exons spanning approximately 80 kb. The disease is inherited as autosomal dominant manner which means one copy of the altered gene in each cell is sufficient to cause the disease. In most of the cases, an affected person inherits the defect from one of the parents.
Sometimes without any genetic history newly mutated gene (de novo mutation in the patient) can also cause the disease. SCN5A was named as BrS1 in late 1990s, the most common form Brugada genotype.
The SCN5A gene, encode the cardiac Na+- channel Nav1.5, affords for making a sodium channel,which in general transports positively charged sodium ions into heart muscle cells. This kind of ion channel plays a pivotal role in initiating a heart beat. Disrupted structure and function of this ion channel due to the mutation in the SCN5A gene causes the reduction of the flow of sodium ions into the cell and interrupt with the normal rhythm of hearts which is a characteristic of Brugada syndrome.
Several mutation have been identified in SCN5A gene in a number of families with idiopathic ventricular fibrillation and these mutations may cause many other arrhythmogenic disease in addition to Brugada syndrome. Long QT syndrome, conduction disease, atrial standstill are some remarkable disease that occurs due to a mutation in SCN5A gene. In contrast to Brugadas yndrome, there is gain of function of ion channel protein in SCN5A gene in long QT syndrome, which causes prolongation of action potential lengthening of the QT interval and increased risk of arrhythmia.
Mutation in SCN10A Gene
SCN10A encode the pore forming alpha subunit of sodium channel, Nav1.8, locates in close proximity to SCN5A in chromosome 3p22. Genome wide association study of SCN10A show that it plays an important role in cardiac conduction disease by influencing the heart rate. Association of this gene with Brugada syndrome is recently studied by Dan Hu et al where mutation frequency in disease condition observed at 16.7%. The study also confers that Brugada patients with SCN10A mutations were more symptomatic and had significant difficulty in heart rate compare to wild type.
A very recent experiment analyze the genome wide Association Study (GWAS) of SCN5A-SCN10A among 912 individuals and significant association signal has found for SCN10A gene.
Mutations in SCN1B Gene
There are four sodium channel beta subunit gene in human and SCN1B encodes the β1-subunit of thecardiac sodium channel which conduct the INa current. The gene ssspans 9.8 kb at chromosome 19q13.1 and is composed of six exons. It has been investigated that, in patient of Brugada syndrome the mutated form of this sodium channel gene loss it's natural function and disrupt the conduction INa current.
Mutations in SCN3B Gene
SCN3B gene encodes the β3 subunit of sodium channel. Mutation in SCN3B gene causes the defective trafficking of sodium current with reduction of Ina in transfected cells. Screening for the association of this gene with Brugada syndrome led to identification of a rare misscense mutation in exon-1 which causes a substitution of leucine to prolin in one of the 179 probands of Brugada patients.
| Brugada Syndrome by Other Gene Mutation|| |
SCN5A gene mutation is found in 20% of patients with Brugada syndrome. To note, Probst et al reported that in families with a familial SCN5A mutation, they found a case with BrS but without the familial mutation meaning the causality of a disrupted SCN5A gene is more complex. So in addition to the sodium channel genes, mutation on other ion channel proteins like k+ channel and Ca2+ homeostasis gene are also reported to associate with some sporadic cases of Brugada syndrome. Genetic segregation pattern of glycerol-3 phosphate dehydrogenase-1 like (GPD1-L) gene is well studied and linkage with other genes have also been studied through the transcriptional analysis of the K+ and Ca2 genes.
Mutation in Gssssslycerol-3 Phosphate Dehydrogenase-1 Like (GPD1-L)Gsseness
Mutation in glycerol-3 phosphate dehydrogenase-1 like (GPD1-L) gene that decreases the trafficking of sodium currents identified as a novel causal factor for Brugada syndrome recently. The gene is composed of eight exons spanning 62 kb atchromosome 3p24–p22.
London et al identified GPD1-L mutation associated with sudden death of infants in a study of large Italian descent family.
In another investigation, among Japanese population on a study group of 80 patient, one synonymous mutation, c.465C>T (p.A155A), as well as one intronic variant, 48-30T>C, were found which were absent in 220 control alleles. In addition, on the same study a single nucleotide polymorphism (*21G>T) in the 3'UTR in 4 patients were also found.
Mutations in CACNA1C gene
CACNA1C gene which code for the pore-forming α1-subunit of the long-lasting (L-type) voltage gated Ca21 channel (Cav1.2) where after splicing, predominant splice form contains 2,138 amino acids. The Cav1.2 channel is activated upon depolarization of the cardiomyocyte, and is responsible for the depolarizing influx of Ca21, the L-type Ca21 current (ICa,L), that inactivates so slowly that it is of major significance for maintaining the plateau phase of the AP. Moreover, it represents a coupling between excitation and contraction byinducing release of Ca21 from the sarcoplasmic reticulum.
Two missense mutations in CACNA1C in 82 Brugada syndrome patients relate CACNA1C gene and Brugada syndrome. It has been investigated that mutation in this gene lead to loss of function of the gene with an impairment of cardiac calcium level conduction.
CACNB2 gene mutatssssion
A regulatory sub unit of calcium channel,CACNB2 gene,code for Calcium channel, voltage-dependent, beta 2 subunit protein that contain 660 amino acid which alter gating, incressasing the ICa, L current. In the C-terminal of CACNB2 gene, due to a missence mutation loss of function correlate the CACNB2 gene with Brugada syndrome.
Mutations in KCNE3 gene
The β subunit of voltage gated potassium channel code by KCNE3 gene consist of three exons and 103 amino acid. This protein regulate several function in conduction of heart potassium current like IKs, IKr, Ito. Several complexities have been associated with the mutation in KCNE3 gene, for example hyper and hypocalamia, thyroid toxicity, periodic paralysis etc. The association of Brugada syndrome with KCNE3 gene mutation is revealed by analyzing six members of a Danish family with Brugada syndrome where over expressed KCNE3 gene causes increased passing potassium current.
Mutation in HEY2 Gene
The gene encodes a basic helix-loop-helix transcriptional regulators of cardiovascular system. Bezzina et al conducted an experiment on mice model to investigate the role of this gene on Brugada syndrome and found a strong correlation with the functionality of this this gene and the disease.
| Acquired Brugada Syndrome|| |
Genetic association of Brugada syndrome has been observed only in 20% of patient and in other causal effect are remained to explore. In some cases unusually high blood levels of calcium (hypercalcemia) or potassium (hyperkalemia), as well as abnormally low potassium levels (hypokalemia) also have strong involvement with acquired Brugada syndrome.
Influence of Drugs on Brugada Syndrome
Several drugs may have influence on exacerbating the condition of Brugada syndrome, so it is urgent to explore the underlying mechanism of this fact. Generally drugs that can induce a distorted heart rhythm include medications used to treat some forms of arrhythmia, angina, high blood pressure, depression, and other mental illnesses are responsible for the formation of acquired Brugada syndrome. Several drugs that exhibit the influential effect of Brugada syndrome as side effect are enlisted bellow-
Tricyclic antidepressants (TCA)
It has been shown from one study that, In case of TCA overdose among 95 person, 10 person displayed type-1 Brugada syndrome like ECG pattern.
Recently it is observed that in two cases Li,which generally used as anti depressant drug,causes the appearance of abnormal type-1 ECG pattern and the withdrawal of the drug promote recurrence of the ECG pattern.
Some first generation antibiotics and antihistamin drugs like dimenhydrinate, diphenhydramine have been elicited for the generation of Brugada syndrome like ECG pattern although the patients didn't have any family history cardiac disease. The antihistamine drugs are also known to induce other arrythmogenic disorder like Long QT syndrome.
Cocaine, Calcium channel blocker, Bupivacaine, Propofol
These drugs are also reported for executing Brugada syndrome like ECG pattern. Cocaine may induce several types of dysrhythmias like accelerated idioventricular rhythm, complete bundle-branch block, complete heart block, ventricular tachycardia, torsade de pointes, ventricular fibrillation, asystole with Brugada like ECG pattern.
Fever Issnducing Brugada Syndrome
Fever or hyperthermia is identified as a causal effect for the exacerbation of severity of Brugada syndrome. In a study it has been documented that, the atypical Brugada ECG pattern is conciliated to normal condition when the augmented body temperature is returned to regular state.
There is an outstanding finding about the temperature mediated regulation of Ina (Na in) voltage-clamp where increased the temperature significantly accelerated both the activation and inactivation kinetics of WT and L325R INa.
It has been observed that, temperature have a potential role on inactivation of ion channel function and a wild type ion channel can act Brugada like pattern during fever.
| Diagnosis of Brugada Syndrome|| |
The abnormality in ECG is considered as hallmark in diagnosis of Brugada syndrome and the atypical ECG pattern which leads to suspect this disease is currently known as the Brugada ECG pattern type1-3. To note, type 1 is the only ECG pattern diagnostic of BrS and type 2 and 3 are not considered BrS. Abnormality is included in both depolarization and repolarization event and in case of repolarization, there are three different types of pattern in observed which are given bellow-
In Type 1 Brugada syndrome, coved shape ST-segment elevation in right precordial leads exhibiting J wave amplitude. ST-segment elevation up to 2 mm or 0.2 mV at its peak followed by a negative T-wave, with little or noisoelectric separation also indicate the type-1 Brugada syndrome.
Type 2 Brugada syndrome also has a high take-off ST segmentelevation but in this case, J wave amplitude (up to 2 mm) gives rise to a gradually descending ST-segment elevation followed by a positive or biphasic T-wave that results in a saddle back configuration.
In Type 3 Brugada syndrome, right precordial ST-segment elevation of 1 mm of saddle back type, coved type or both can be appeared.
A number of factors other than Brugada syndrome are responsible for the elevation of ST segment in ECG. So following additional observation should be considered for excluding other factors and diagnosed Brugada syndrome without any background noise-
- Coved type ST segment elevation independent of the sodium channel blocker in more than one precordial leads including ventricular fibrillation, ventricular tachycardia, family history of getting similar type ECG pattern, electro physiological inducibility, syncope,nocturnal agonal respiration.
- Usspon challenging by a sodium channel blocker,elevation of the saddle back type S-T segment to a value >2mm.
- Tssype 3 ST segment elevation after treated with sodium channel blocker.
Though these three types of ECG patterns are known to distinguish Brugada syndrom from other cardiac diseases, only coved type ST segment elevation pattern is practically used in diagnosis of Brugada syndrome.
| Management of Brugada Syndrome|| |
Replacements of electrolytes, avoiding the drugs that exacerbate the symptoms of Brugada syndrome, provide antipyretic agents for regulating body temperature are some feasible management of Brugada syndrome.
The severity of the disease may also be ameliorated by vagotonic agents, α-adrenergic agonists, ß-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin. Implantable cardioverter-defibrillator (ICD) is the only established effective device treatment for the disease though the complication rate is high in this case. Quinidine, denopamine, cilostazol, orbepridil are effective in VF suppression during long-termoral therapy. Quinidine may have some side-effect but recently low dose of quinidine is recognized as benign in this case. Some isoprenaline infusion increases Ca+ current and is helpful in emergency treatment of arrhythmic storms in Brugada syndrome.
During more stubborn cases recurrent ventricular arrhythmic events even under quinidine, where medicinal therapy is not enough to normalize the abnormal ECG pattern, ablation can be used. Especially the epicardial ablation is quite effective and this fact was observed in a study, where out of nine patients five were responded very we. Significant suppression of abnormal ventricular fibrillation was demonstrated in catheter ablation treatment and the fact was experimented on the same study with an observation of nonrecurrence of atypical VT/VF.Incidence observed in seven of the nine patients (78%)in this case.
During pregnancy, hormonal change may cause severe problem in women with Brugada synedrome.In this case intravenous infusion of low-dose isoproterenol and quinidine helps to ameliorate the severity.
| Conclusion|| |
Sudden unexpected death and Lack of detail pathopysiological mechanism give Brugada syndrome a an enigmatic sound. Furthermore the diseases is more prevalent in Southeast Asian region which promted the researchers of this area to reveal it's actual causal factors. Though primarily it is recognized as a genetic and male dominant disorder, there are several other factors that may initiate or augment the disease condition. In this context we want to make an overview about it's genetic susceptilibility with other acqured phenomena,epidemiology,diagnosis and management system.
| Conflicts of Interest|| |
The authors have no conflicts of interest to submit the article in this journal.
| Acknowledgement|| |
Authors are thankfull to the UGC grant, Higher Education Quality Enhancement Project (HEQEP),CP-2057.
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