Brugada syndrome

It is recommended that all first degree relatives of a person diagnosed with Brugada syndrome have an electrocardiogram (ECG/EKG). If there are other relatives at risk, they should also have electrocardiogram. If a gene change for Brugada syndrome has been identified in the family, all at risk relatives can have testing for just that one gene change.

Brugada Foundation (or Fundacion Brugada), based in Spain, [link url="www.brugada.org” target=”_blank”>www.brugada.org
Sudden Arrhythmia Death Syndromes (SADS) Foundation, [link url="www.sads.org” target=”_blank”>www.sads.org
Canadian SADS Foundation, [link url="www.sads.ca” target=”_blank”>www.sads.ca

For Brugada syndrome, an implantable cardioverter defibrillator (ICD) is currently the only effective treatment in prevention of severe abnormal heartbeats and sudden cardiac death. A drug called isoproterenol is used to prevent electrical storms (along with an ICD).

Typically, people who have abnormal heart rhythm syndromes like, Brugada syndrome, are referred to a special type of cardiologist called an electrophysiologist (EP). The Heart Rhythm Society has a tool to help find an electrophysiologist in your area.

There are several recommendation for prevention of symptoms and/or maintenance of symptomatic people with Brugada syndrome.

Brugada syndrome type 1, or Brugada syndrome 1 (BRGDA1), refers to Brugada syndrome caused by gene changes in the SCN5A gene. Approximately 15-30% of people with Brugada syndrome have changes in this particular gene. It is passed on in families in an autosomal dominant manner which means that people only need to have one gene change to develop the condition. This condition typically starts in adulthood and has an average age of sudden death of 40-years-old.

The onset of Brugada syndrome typically begins in adulthood; however, the age at diagnosis can range from infancy to late adulthood. The average age of sudden cardiac death is 40 years.

Brugada sign refers to a specific pattern on an EKG (electrocardiogram). It is possible to have the Brugada sign or pattern and not have Brugada syndrome.

Typically, the most common first symptom in Brugada syndrome is an individual in their 40s who has severe arrhythmias and a history of passing out. The medical term for passing out is syncope. Syncope is a common presenting symptom.

Brugada syndrome is a cardiac condition disorder. This means that it affects how the electrical pulse move through the heart. It typically occurs in an affected person’s 40s; however, the youngest reported age was two days of life and the oldest reported age was 85. Brugada syndrome should be suspected in any person who has a personal history of unexplained passing out (syncope) and/or heart attack, a specific abnormal heart beat pattern on an EKG, and/or a family history of sudden cardiac death (SCD).

Brugada syndrome type 9 (BRGDA9) refers to Brugada syndrome caused by changes in the KCND3 gene. Changes in the KCND3 gene can also cause spinocerebellar ataxia and susceptibility to long QT syndrome.

Brugada syndrome type 8 (BRGAD8) refers to Brugada syndrome caused by changes in the HCN4. No other conditions are known to be caused by changes in this gene.

Brugada syndrome type 7 (BRGDA7) refers to Brugada syndrome caused by changes to the SCN3B gene. Changes to the SCN3B gene can also cause familial atrial fibrillation.

Brugada syndrome type 6 (BRGDA6) refers to Brugada syndrome caused by changes is the KCNE3 gene. Changes to this gene can also cause hyperkalemic periodic paralysis.

Brugada syndrome type 5 (BRGDA5) refers to Brugada syndrome caused by changes in the SCN1B gene. People who have Brugada syndrome because of changes in the SCN1B gene also have other conduction abnormalities. Conduction abnormalities are problems with how the electrical current moves through the heart; the electrical current often gets "blocked." Changes in the SCN1B can also cause temporal lobe epilepsy, generalized epilepsy with febrile seizures plus type 1 (GEFS+1), and atrial fibrillation.

Brugada syndrome type 4 (BRGDA4) refers to Brugada syndrome caused by gene changes in the CACNB2 gene. People who have Brugada syndrome due to changes in the CACNB2 gene have the typical pattern on EKG and slightly shorter QT intervals. This is interesting because in people who have a different type of change in the CACNB2 gene and do not have Brugada syndrome, have a different abnormal heart rhythm condition called long QT syndrome (as opposed to short QT syndrome).

Changes in the CACNB2 gene can also cause Lambert-Eaton myasthenic syndrome.

Brugada syndrome type 3 (BRGDA3) refers to Brugada syndrome caused by changes in the CACNA1C gene. Changes in this gene can also cause long QT syndrome and susceptibility to malignant hyperthermia.

Brugada syndrome type 2 (BRGDA2) refers to Brugada syndrome cased by changes in the GPD1L gene. No other genetic conditions are known to be associated with changes in this gene.

Brugada syndrome type 1, or Brugada syndrome 1 (BRGDA1), refers to Brugada syndrome caused by gene changes in the SCN5A gene. Approximately 15-30% of people with Brugada syndrome have changes in this gene. It is passed on in families in an autosomal dominant manner which means that people only need to have one gene change to develop the condition. This condition typically starts in adulthood and has an average age of sudden death of 40-years-old.

There may be several explanations when a family history appears negative for Brugada syndrome. A family history may appear negative due to failure to recognize the condition in the family due to incomplete penetrance (relatives who have a gene change but do not develop symptoms), early death of the affected parent before symptoms start, or late onset of symptoms. Also, non-paternity or non-maternity could be considered. Non-paternity means that a man is not the biological father of a person. Non-maternity means that a woman is the not biological mother of a person. Non-maternity is rare and can happen in the setting of egg donation or surrogacy, for example. Also, someone may not know they are adopted and so they assume they do not have a family history.

There is also the possibility that an affected person may have a de novo gene change for Brugada syndrome. The word de novo stands for "new." In this case a person could be the first family member to have a causative gene change.

Lastly, there is a possibility for gonadal mosaicism. Gonadal mosaicism means that a person only has a gene change in their egg cells or sperm cells and not in the rest of the cells of their body. This is a possibility for any inherited condition; however, it has not been reported in Brugada syndrome.

There are approximately 23 genes known to be associated with Brugada syndrome. Approximately 15-30% of causative gene changes are in the SCN5A gene. Gene changes in the SCN5A gene can also cause Long QT syndrome type 3 which is a different type of inherited abnormal heart rhythm condition. Brugada syndrome and long QT syndrome have different patterns on EKG, so they are usually easy to tell apart.

Brugada syndrome should be suspected for anyone who has recurrent passing out (syncope), ventricular fibrillation.

To establish the extent of disease in people who are newly diagnosed with Brugada syndrome, several evaluations are needed after an initial diagnosis. Electrocardiogram to assess for the characteristic ST-segment elevation in leads V1 to V3. In people with type 2 EKG or type 3 EKG and suspicion of the disease. There individuals will need induction with sodium blockers. Electrophysiologic study to assess risk of sudden cardiac death. And, consultation with a clinical geneticist or genetic counselor to discuss the genetic component of the disease. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

If there is a suspicion for Brugada syndrome or a family history of Brugada syndrome, seeing a genetic specialist can be helpful. The genetic specialist can ask questions about the family history and recommend genetic testing if appropriate. The family history would help to identify family members that may be at risk to have Brugada syndrome. Relatives at risk can also have an EKG. This would enable family members to seek preventative measures for themselves and would help them to avoid medications that can cause ventricular arrhythmias. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

There is no newborn screening for Brugada syndrome. However, if a gene change has been identified in the family, testing on cord blood is possible to determine if an infant is affected.

Brugada syndrome can often be clinically diagnosed (or at least suspected) by finding a specific pattern on an EKG. It is important to note that sometimes people can have that pattern on EKG and NOT have Brugada syndrome. It is also important to remember that, though unusual, people who have Brugada syndrome may not have the characteristic pattern on EKG since it can be masked by other health problems and medications.

The website [link url="clinicaltrials.gov” target=”_blank”>clinicaltrials.gov is a good resource to find clinical research on many conditions including Brugada syndrome.
In Europe, the EU Clinical Trial Register performs a similar service.
To learn about clinical trials sponsored by private sources, you can contact www.centerwatch.com.

For individuals with Brugada syndrome who have a history of passing out suddenly and/or a history of heart attack, implantable cardioverter defibrillators (ICDs) are the only currently effective therapy for sudden cardiac death. Isoproterenol is also recommended along with ICDs for treatment of electrical storms (when the heart does not beat correctly).

Hormonal changes during pregnancy can cause abnormal heart beats for women with Brugada syndrome. A low-dose of the medication, isoproterenol, through IV infusion followed by a medication taken orally called, quinidine, can normalize an abnormal fast heart beat.

Quinidine is not known to increase the risk for adverse pregnancy outcomes such as birth defects and miscarriage. It is the preferred medication to treat abnormal heart beats during pregnancy. A good resource to learn more about pregnancy risks due to exposure to medications or other agents is [link url="www.mothertobaby.org” target=”_blank”>www.mothertobaby.org. Isoproterenol has not been well-studied during pregnancy; however, a small study did not find an increased risk for adverse pregnancy outcome in women exposed in the first trimester.

Most often, Brugada syndrome is inherited in an autosomal dominant manner. This means that having just one gene change in a Brugada syndrome gene is enough to cause symptoms of the condition. There is one gene associated with Brugada syndrome, the KCNE5 gene, that is inherited in an X-linked manner. This means that mothers are carriers and they pass their gene change for Brugada syndrome onto sons.

Most often, Brugada syndrome is inherited in an autosomal dominant manner. This means that having just one gene change for Brugada syndrome is enough to cause symptoms.

It can be scary sending your child with Brugada syndrome to a school that may not be familiar with abnormal heart rhythm syndromes and that may not have lifesaving equipment if a child goes into cardiac arrest. The [link url="www.sads.org” target=”_blank”>Sudden Arrhythmia Death Syndromes Foundation (SADS) website has a lot of resources and forms for schools, school nurses, and parents with recommendations and suggestions on how to make a school safe. There is also a section of the website that is designed for kids who are affected and living with these conditions. It’s called SADSConnect For Youth.

When Brugada syndrome is suspected, it is helpful to discuss the availability of genetic testing with a genetics professional. Approximately 75% of affected people will have a clinical diagnosis based on their personal history and EKG results. Genetic testing can confirm the diagnosis. The SCN5A gene is the most common gene associated with Brugada syndrome accounting for 15-30% of cases. Sequencing (reading through the entire genetic code of a gene) can be performed first. If that is normal, deletion and duplication testing (looking for small missing or extra pieces of the gene) can be performed next. A multigene panel (large gene panel) that includes all of the genes known to be associated with Brugada syndrome can also be considered. This would test all of the genes of interest at the same time.

The website [link url="clinicaltrials.gov” target=”_blank”>clinicaltrials.gov is a good resource to find clinical research on many conditions including Brugada syndrome.
In Europe, the EU Clinical Trial Register performs a similar service.
To learn about clinical trials sponsored by private sources, you can contact www.centerwatch.com.

The [link url="www.sads.org” target=”_blank”>Sudden Arrhythmia Death Syndrome Foundation (SADS) has a function on the website where you can find an experienced doctor in your area that can treat your Brugada syndrome.

The [link url="www.hrsonline.org” target=”_blank”>Heart Rhythm Society website also has a function that helps you search for an electrophysiologist (EP) in your area.

The discovery of Brugada syndrome as it’s own specific cardiac disease is relatively new. The actual population prevalence is unknown. It occurs in men and women but appears to affect men more often. Brugada syndrome has also been reported in all ethnic populations; however, it some populations it is referred to by a different name (ie. sudden unexplained nocturnal death syndrome- SUNDS- in the Southeast Asian population).

Brugada syndrome does not affect a person’s physical development and it does not affect intelligence.

Not everyone with Brugada syndrome has an affected parent. The de novo rate for Brugada syndrome is estimated to be approximately 1%. The word de novo means "new;" therefore, an individual with a de novo gene change for Brugada syndrome would be the first person to have the condition in the family. In this case, the affected person’s parents, siblings, and other family members would not be at risk. However, the affected person’s children would have a 50% chance to inherit Brugada syndrome.

Not everyone with Brugada syndrome will have symptoms. Some people may be at risk to develop Brugada syndrome but live their whole lives without symptoms. Sometimes, people can show the characteristic "Brugada sign" on EKG but not show the physical symptoms of the syndrome. Also, sometimes, the first symptom is sudden death and it may not be recognized that the person was at risk due to Brugada syndrome.

The genes that cause Brugada syndrome can also cause several other genetic conditions, such as: long QT syndrome, short QT syndrome, dilated cardiomyopathy, malignant hyperthermia susceptibility, spinocerebellar ataxia, and atrial fibrillation. There are many other conditions that can also be caused by changes to these genes. For a complete list, you can find the [link url="www.ncbi.nlm.nih.gov/books/NBK1517″ target=”_blank”>gene review for Brugada syndrome and refer to Table 2.

The genes GPD1L, HCN4, and RANGRF are not know to cause any other genetic conditions besides Brugada syndrome.

Things that should be avoided for Brugada syndrome include:

There is one gene for Brugada syndrome, KCNE5, that is passed on in an X-linked manner. This means that mothers pass the gene change onto their sons. Based on reports in the literature, only one family has been found to have changes in the KCNE5 gene associated with symptoms of Brugada syndrome.

In the Southeast Asian population, Brugada syndrome is known as sudden unexpected nocturnal death syndrome (SUNDS). Multiple studies have determined that Brugada and SUNDS are, for all intents and purposes, the same condition. Other names for SUNDS include: sudden and unexpected death syndromes (SUDS), bangungut in the Philippines, non-lai tai in Laos, lai-tai in Thailand, and pokkuri in Japan.

Brugada Foundation (or Fundacion Brugada), based in Spain, [link url="www.brugada.org” target=”_blank”>www.brugada.org
Sudden Arrhythmia Death Syndromes (SADS) Foundation, [link url="www.sads.org” target=”_blank”>www.sads.org
Canadian SADS Foundation, [link url="www.sads.ca” target=”_blank”>www.sads.ca

There are disadvantages to having an ICD in Brugada syndrome, though it is important to remember that an ICD is a life-saving treatment and it is the only current therapy for the prevention of sudden cardiac death. For many patients who do not have symptoms, but ICD therapy is still indicated, there is an adjustment to having this device their entire lives. The lithium battery in an ICD can last up to seven years. Therefore, patients will likely need to have their ICD replaced several times throughout their lives. Some people who have ICDs may also experience "inappropriate" shocks (shocks from an ICD that were unnecessary). There are also many circumstances that can interfere with how your ICD works. Certain medical equipment can interfere with how your ICD works. For example, having an MRI or MRA when you have an ICD is not recommended. When traveling with an ICD it is important to be aware that it can set off security scanners in airports. While talking on your cellphone is fine, it is recommended that you avoid placing your phone within six inches of your implantation site. The American Heart Association recommends refraining from driving for at least six months following ICD placement if your ICD was placed due to cardiac arrest or ventricular arrhythmia. If your ICD has not fired within those six months, you’ll likely be able to drive again.

For those individuals living with Brugada syndrome, there are also many circumstances that can interfere with how your ICD works. Certain medical equipment can interfere with how your ICD works. For example, having an MRI or MRA when you have an ICD is not recommended. When traveling with an ICD it is important to be aware that it can set off security scanners in airports. While talking on your cellphone is fine, it is recommended that you avoid placing your phone within six inches of your implantation site. The American Heart Association recommends refraining from driving for at least six months following ICD placement if your ICD was placed due to cardiac arrest or ventricular arrhythmia. If your ICD has not fired within those six months, you’ll likely be able to drive again.

Devices that are not thought to interfere with how your ICD works include: microwave ovens, televisions and remote controls, AM/FM radios, toasters, electric blankets, electric shavers and electric drills, computers, scanners, printers, and GPS devices.

One genetic testing challenge for Brugada syndrome, is that there are approximately 23 genes associated; however, only one gene is common for Brugada syndrome (SCN5A) and accounts for 15-30% of causes. The other genes all account for less than 7% of cases of Brugada syndrome suggesting that these cases may represent private, familial mutations and testing of all 23 genes may not be beneficial for the majority of patients. Additionally, the genes associated with Brugada are also associated with other genetic syndromes, and it is often challenging to predict a person’s potential symptoms based on their genetic testing result.

Currently there are not any guidelines or restrictions on physical activity or exercises specifically for people with Brugada syndrome. Nevertheless the American Heart Association does recommend safe guidelines for athletic participation of young athletes diagnosed with genetic cardiovascular diseases. Even with insufficient data on the risks of exercise in patients with Brugada syndrome, it is still suggested that they be restricted from vigorous exercise and activities such as body building and hockey due to the possibility of worsened ST abnormalities and possible production of ventricular arrhythmias. Activities that are most likely safe for people with Brugada syndrome include doubles tennis, bowling, golf, walking, and biking.

It is well known that genetic factors and environmental factors can contribute to "how affected" a person is by a genetic condition including Brugada syndrome. There is a change in the SCN5A gene that is called a polymorphism. A polymorphism is a change in a gene that is identified in a certain percentage of people in the general population, general 1%. the A polymorphism does not cause disease. A polymorphism in the SCN5A gene called p.H558R is present in 20% of the general population. Based on many studies, this gene change partially restores the sodium current (passage of sodium ions in the cells) which typically causes more mild symptoms of Brugada syndrome.

There can be adverse affects/disadvantages to having an ICD in Brugada syndrome, though it is important to remember that an ICD is a life-saving treatment. For many patients who do not have symptoms, but ICD therapy is still indicated, there is an adjustment to having this device their entire lives. The lithium battery in an ICD can last up to seven years. Therefore, patients will likely need to have their ICD replaced several times throughout their lives. Some people who have ICDs may also experience "inappropriate" shocks (shocks from an ICD that were unnecessary).

Other risks are rare, but can include: