Course:MEDG550/Student Activities/Brugada Syndrome

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Brugada syndrome (also known as sudden unexpected nocturnal death syndrome or SUNDS) is a genetic condition where the electrical signals that control how the heart beats are abnormal. It is caused by mutations in the gene SCN5A. Individuals with Brugada syndrome may have abnormal heart rhythms, unexplained fainting spells, and are at risk for sudden death. Current treatment includes surveillance of the condition, avoidance of triggers, and surgery to implant an implantable cardioverter-defibrillator (ICD)[1].

Changes in Heart Function

When functioning as expected, the heart cycles through two stages. When the heart is relaxed, blood flows in and fills the chambers of the heart. The muscles that control the heart then contract, pumping blood out to the body. These stages repeat in a constant cycle, and this cycle of contracting and relaxing is controlled by electrical signals. The electrical signal travels through the heart, from one cell to another, through changes in the amounts of different molecules (sodium, potassium, calcium), in each of the cells. As these molecules move in and out of the heart cells, they move the electrical signal throughout the heart, telling the muscles when to contract and relax.

In individuals with Brugada syndrome, a sodium channel is not working as expected. The sodium channel acts like a “gate” that lets the molecule sodium move in and out of the heart cells. When this channel isn’t working as expected, the electrical signals telling the heart how to beat are disrupted, which leads to irregular heart rhythms (arrhythmias). This may cause an individual to pass out, because not enough blood is being pumped to the brain. Without treatment, these irregular rhythms can also cause the heart to stop completely (cardiac arrest)[2].

See Genetics for more information on the causes of changes.

Clinical Features

An individual with Brugada syndrome usually first shows symptoms in their 30’s or 40’s. However, symptoms can be observed earlier in childhood or infancy, or may never manifest [1][3][4][5] .

Common symptoms of Brugada syndrome include:

  • Irregular heartbeats
  • Loss of consciousness (fainting)
  • Gasping or labored breathing during sleep
  • Sudden cardiac death

These symptoms occur as a result of irregular heart rhythms, are most common during rest, or while sleeping[6].

These events may be triggered by a number of factors including[6]:

  • Fever
  • Cocaine use
  • Consumption of excessive amounts of alcohol
  • Certain medications·      

Brugada syndrome has also been shown to be the cause of some cases of sudden infant death syndrome (SIDS) during the first year of life[5].

Prevalence

Brugada syndrome is estimated to occur in approximately 1 in 2000 people worldwide, and is seen most frequently in individuals of Southeast Asian, and European ancestry. While it can affect both men and women, symptoms are approximately eight times more common in men than women. This difference between men and women is thought to be due to the influence of testosterone[3].

History

Brugada syndrome is one of several conditions known to result in sudden arrhythmic death (SAD). A higher prevalence of SAD during sleep among individuals of Southeast Asian ancestry was noted in several studies throughout the 1980’s[7]. Subsequent research lead to the identification of unique abnormal cardiac electrical signaling patterns in affected individuals, now known as Brugada syndrome. While the name “Brugada syndrome” was first coined in 1996[8], references to this condition can be seen in South East Asian folklore, indicating a long history of this condition within this population. In the Philippines, Laos, and Thailand, SAD is commonly referred to as bangungot, and according to folklore is the result of malevolent supernatural beings. While the cause of Brugada syndrome is now known, many aspects of this condition are accurately referenced within traditional folklore. These include the recognition of a higher prevalence among young men, death often occurring during sleep, and that large meals and excessive alcohol consumption may be triggers. However, beliefs regarding bangungot, such as symptoms, risk factors, and preventative measures, can vary between communities[9]. It may therefore be important for genetic counselors and other care providers to address these perceptions with patients in order to convey accurate medical information.

Diagnosis and Testing

A diagnosis of Brugada syndrome may be suspected if an individual has[10]:

  • A history of unexplained fainting episodes,
  •  A family history of sudden unexplained death
  • Cardiac arrest, with a physically normal heart
ECG of a heart with a normal heart rhythm.

An electrocardiogram (ECG) is used to confirm a diagnosis of Brugada syndrome, as well as to clarify the severity of the disease in an affected individual. An ECG is a test that measures the electrical signals of the heart and looks for irregular rhythms. An electrical signal seen on an ECG appears as a “spike”. In Brugada syndrome, this spike lasts longer than it should. Two types of abnormal patterns may be observed:

  • Type 1 ECG pattern is the more severe pattern. The spike from an electrical signal lasts significantly longer than it should. This pattern must be seen for someone to be diagnosed with Brugada syndrome.
  • Type 2 ECG pattern looks similar to a Type 1 pattern, but the elongation of the spike is less noticeable. A Type 2 ECG pattern is suggestive of Brugada syndrome, but is not sufficient for a diagnosis[4].

Some drugs, known as “sodium blockers” can trigger irregular ECG rhythms in individuals susceptible to Brugada syndrome. In cases where an individual suspected to be at risk for Brugada syndrome has a normal or Type 2 ECG pattern, these drugs may be given in a medical setting to trigger an irregular heart rhythm. If these drugs cause a type 1 ECG pattern, then this confirms a diagnosis of Brugada syndrome[4].

Genetic testing can support the diagnosis of Brugada syndrome. Single gene testing can look for changes in the gene SCN5A. A genetic change in this gene can be found in approximately 30% of patients with Brugada syndrome[11]. If a change in this gene is found, it can provide a possible explanation for the symptoms, and assist with assessing at-risk family members. If a change in this gene is not found, it does not influence treatment decisions as those decisions are still based on the heart rhythm that is seen[4].

Treatment and Management

While no cure for Brugada syndrome exists, there are a number of options to decrease the risk to individuals.

Illustration of a implantable cardioverter defibrillator (ICD) showing its location and connection to the heart.

Implantable Cardioverter - Defibrillator (ICD): An ICD is a device that is surgically implanted into the upper chest and is connected to he heart by wires. It provides electrical signals to control the heart rate and prevent abnormal heart rhythms or cardiac arrest. ICD’s are recommended for high-risk individuals, those with a history of fainting or previous cardiac arrest, to prevent future cardiac arrest. They may also be provided to patients who have shown no previous symptoms but who have abnormal heart rhythms on their ECG test[4].

Surveillance: If an individual is at risk for Brugada syndrome but has no symptoms it is recommended that they receive an ECG every one to two years, starting from birth or the time of diagnosis to monitor their condition[4]. If an abnormal ECG is observed, then further intervention may be taken (see above).

Medications and situations to avoid: Alongside medical intervention, it is important to avoid situations that may trigger an irregular heart rhythm. This includes avoiding use of recreational drugs like cocaine, and avoiding consuming large amounts of alcohol. Fevers can trigger irregular heart rhythms and should be treated quickly with medication[10].

Some prescription medications are known to trigger irregular heart rhythms in individuals with Brugada syndrome. Any new prescriptions and medications can be checked to ensure they are safe at BrugadaDrugs.org. This website provides up to date information on drugs that may be harmful for individuals with Brugada syndrome.

The symptoms of Brugada syndrome can sometimes be misinterpreted as a heart attack when presenting to the emergency room. It is suggested that individuals with Brugada syndrome carry a copy of their ECG pattern with them to avoid misinterpretation and faster treatment if an emergency occurs.

Genetics

Genetic Changes

The information that tells the body how to grow, develop, and function is contained within our DNA. This information is organized into many smaller sections called “genes”. Each gene can be read and interpreted by our body to make a product that will play a role in how our body functions. When one of these genes is altered, the product it makes can be disrupted and no longer function properly.

Brugada syndrome is caused by changes in the gene SCN5A[2][4]. This gene makes a sodium channel, which acts like a gate to let sodium into the heart. This movement of sodium into the heart is an important part of how electrical signals move through the heart, to control how the heart beats. The changes in this gene that cause Brugada syndrome prevent the channel from allowing sodium into the heart as effectively. This leads to the electrical signal to some parts of the heart being blocked, and can cause the irregular heart rhythms associated with Brugada syndrome[2].

Autosomal dominant inheritance where an affected parent has a 50% chance of passing on the mutation to each of their children. The affected parent can be either male or female.

Inheritance

Humans have two copies of every gene, one inherited from our mother, and one from our father. Brugada syndrome is inherited in an autosomal dominant way[1][4][5]. This means that only one of the two SCN5A genes needs to be changed for a person to have the condition. The other copy is usually still present and functioning as expected, but it is not able to compensate for the changed copy.

When a person has children, they pass on one of their two copies of the gene to each of their children. This means that they have a 50% chance of passing on the changed copy, and the condition, to each of their children.

While most people inherit Brugada syndrome from a parent, approximately 1% of individuals have a change that is de novo, meaning that the change first occurred in them, and was not inherited from a parent[5].

Differences in symptom severity

It is difficult to predict the severity of symptoms of individuals with Brugada syndrome. Of all individuals who have a harmful genetic change in SCN5A, approximately 20-30% will show un-triggered arrhythmias characteristic of Brugada syndrome on an ECG[5].

The age and severity at which symptoms appear can also vary between individuals. In some cases, individuals first symptoms are fainting episodes, or gasping breathing during sleep. However, in other cases the first sign of the condition is sudden cardiac arrest. While the average age of onset for these symptoms is in the 30’s or 40’s, they can also occur in babies or children, or may not occur until much later in life. Some individuals with the genetic change may never show symptoms[3][5].

This variation occurs even among family members who have identical changes in the SCN5A gene[3].

Genetic Counselling

Genetic counsellors provide individuals with genetic conditions with information and support to help them make decisions about their health care, as well as options for their children and future pregnancies.

Genetic testing:

For individuals with a suspected diagnosis of Brugada syndrome, genetic testing can confirm the diagnosis in the individual. Additionally, if a genetic explanation is found for their condition, genetic testing can then be offered to unaffected relatives to identify those who are at risk and require medical surveillance.

Because Brugada syndrome is a genetic condition, family members of an individual diagnosed with this condition are also at risk. If the specific genetic change was identified in an affected family member, asymptomatic family members are also able to get genetic testing to identify who needs further surveillance by ECG, and to determine lifestyle changes that may need to be made. If the genetic change is unknown, at-risk relatives should be screened by ECG to identify their risk[3].

Preconception counselling and prenatal diagnosis: Individuals with Brugada syndrome have a 50% chance of passing the condition on to their children. Due to this risk, if the genetic change present in an affected parent is known, prenatal testing is available in future pregnancies to determine if the fetus is at risk for Brugada syndrome[5].

In prenatal diagnosis genetic testing is performed on fetal cells, collected by chorionic villus sampling (CVS, where a small amount of the placenta is taken for testing), or by amniocentesis (where a small amount of the fluid around the fetus is collected for testing). If IVF is being used for conception, pre-implantation diagnosis can also be used to screen for Brugada syndrome.

Psychosocial Implications:

Given that one of the first symptoms of Brugada syndrome is sudden cardiac death, it can feel frightening to receive a diagnosis of Brugada syndrome in the family. Individuals with symptoms of Brugada syndrome may experience fear of severe symptoms, uncertainty about the future, and guilt or concern for their relatives. Unaffected family members of individuals with Brugada syndrome may experience relief, guilt, or difficulty accepting lifestyle changes. During a genetic counselling appointment, individuals can discuss these feelings of fear, guilt, uncertainty, or any other emotions that arise from a new diagnosis. Genetic counsellors can also provide resources for medical information and psychosocial support in the community.

Patient Resources

BrugadaDrugs.org. https://www.brugadadrugs.org/

Genetic Counselling – find a clinic https://www.cagc-accg.ca/?page=225

BC Inherited Arrhythmias Program http://www.cardiacbc.ca/our-services/programs/bc-inherited-arrhythmia-program

Rare Diseases Database - Brugada syndrome https://rarediseases.org/rare-diseases/brugada-syndrome/

References

  1. ↑ 1.0 1.1 1.2 Gehshan, J.; Rizzolo, D. (2015). "Understanding Brugada Syndrome". Journal of the American Academy of Physician Assistants. 28: 32–36.
  2. ↑ 2.0 2.1 2.2 Blok, M. and Boukens, B.J., 2020. Mechanisms of Arrhythmias in the Brugada Syndrome. International Journal of Molecular Sciences, [online] 21(19), p.7051. Available at: <https://www.mdpi.com/1422-0067/21/19/7051>.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Isbister, J.C., Krahn, A.D., Semsarian, C. and Sy, R.W., 2020. Brugada Syndrome: Clinical Care Amidst Pathophysiological Uncertainty. Heart Lung and Circulation, [online] 29(4), pp.538–546. Available at: <https://doi.org/10.1016/j.hlc.2019.11.016>.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Brugada, J., Campuzano, O., Arbelo, E., Sarquella-Brugada, G. and Brugada, R., 2018. Present Status of Brugada Syndrome. Journal of the American College of Cardiology, [online] 72(9), pp.1046–1059. Available at: <https://linkinghub.elsevier.com/retrieve/pii/S0735109718353622>.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Brugada R, Campuzano O, Sarquella-Brugada G, et al. Brugada Syndrome. 2005 Mar 31 [Updated 2016 Nov 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1517/
  6. ↑ 6.0 6.1 Pappone, C. and Santinelli, V., 2019. Brugada Syndrome: Progress in Diagnosis and Management. Arrhythmia & Electrophysiology Review, [online] 8(1), pp.13–18. Available at: <https://www.aerjournal.com/articles/brugada-syndrome-management>.
  7. ↑ Munger, R.G. (1987). "Sudden death in sleep of Laotian-Hmong refugees in Thailand: a case-control study". American Journal of Public Health. 77: 1187–1190.
  8. ↑ Yan, G.X. (1996). "Cellular Basis for the Electrocardiographic J Wave". Circulation. 93: 372–279.
  9. ↑ Abad, P.J. (2014). "Cultural beliefs on disease causation in the Philippines: challenge and implications in genetic counseling". Journal of Community Genetics. 5: 399–407.
  10. ↑ 10.0 10.1 Gourraud, J.-B., Barc, J., Thollet, A., Le Marec, H. and Probst, V., 2017. Brugada syndrome: Diagnosis, risk stratification and management. Archives of Cardiovascular Diseases, [online] 110(3), pp.188–195. Available at: <http://dx.doi.org/10.1016/j.acvd.2016.09.009>.
  11. ↑ Snir, A.D. and Raju, H., 2019. Current Controversies and Challenges in Brugada Syndrome. European Cardiology Review, [online] 14(3), pp.169–174. Available at: <https://www.ecrjournal.com/articles/Current-Controversies-Challenges-Brugada-Syndrome>.
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