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Copyright 2006, 2013
NORD is very grateful to Joseph Kim, NORD Editorial Intern from the University of Notre Dame, and Ramon Brugada, MD, PhD, Girona Institute of Biomedical Research IDIBGI and School of Medicine, University of Girona, Girona, Spain, for assistance in the preparation of this report.
Brugada syndrome is a rare inherited cardiovascular disorder characterized by disturbances affecting the electrical system of the heart. The main symptom is irregular heartbeats and, without treatment, may potentially result in sudden death. In some cases, no symptoms may precede sudden death. Brugada Syndrome typically begins onset in adulthood and follows autosomal dominant inheritance. The prevalence rate of the disease is currently unknown due to its recent identification.
The normal heart has four chambers. The two upper chambers are known as the atria and the two lower chambers are known as the ventricles. Electrical impulses cause the heart to beat. In individuals with Brugada syndrome, the electrical impulses between the ventricles become uncoordinated (ventricular fibrillation) resulting in decreased blood flow. Decreased blood flow to the brain and heart may result in fainting or sudden death.
Brugada syndrome is named by the Spanish cardiologists Pedro Brugada and Josep Brugada who reported it as a distinct clinical syndrome in 1992.
An affected individual with Brugada syndrome typically begins to show symptoms around the age of 40. Individuals with Brugada syndrome may experience irregular heartbeats (ventricular arrhythmias) or may have no apparent symptoms (asymptomatic). Irregular heartbeats may cause difficulty breathing, loss of consciousness or fainting (syncope), and sudden death.
The severity of symptoms varies from case to case. There are some known triggers for Brugada syndrome, like fever and sodium blocking drugs.
A specific presentation of Brugada syndrome is known as sudden unexpected nocturnal death syndrome (SUNDS). SUNDS is prevalent is Southeast Asia and occurs in young individuals, who die from cardiac arrest during sleep with no apparent or identifiable cause. Another presentation of Brugada syndrome is sudden infant death syndrome (SIDS), which is the death of a child within the first year of life without an identifiable cause.
Brugada Syndrome is caused mainly by a sodium channelopathy (mutations in SCN5A), which is a disturbed functioning of sodium channel subunits or proteins that regulate them. Dysfunction of the sodium channels leads to local conduction blockages in the heart.
Mutations in other genes (GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, SCN3B, and HCN4) are also known to cause Brugada syndrome. These mutations are inherited in an autosomal dominant manner from parents to their children. This means only a single copy of an abnormal gene is necessary for the appearance of the disease in an individual. Most individuals with the disease also have an affected parent. Each child of an affected individual has a 50% chance of inheriting the genetic variation, regardless of the sex of the individual.
The primary gene known to be associated with Brugada syndrome is located on chromosome 3 and has been termed the SCN5A gene. Approximately 15-30% of individuals with Brugada syndrome have a SCN5A gene mutation. This gene is responsible for the production of a protein that allows movement of sodium atoms into heart muscle cells through a channel called the sodium channel. Abnormalities in the SCN5A gene change the structure or function of the sodium channel and result in a reduction of sodium into the heart cells. Reduced sodium can lead to an abnormal heart rhythm that can lead to sudden death. SCN5A gene mutations are also associated with the long QT syndrome type 3 (LQT3), which is one form of a heart rhythm abnormality called Romano-Ward syndrome. Some families have been reported that have relatives with Brugada syndrome and LQT3, suggesting that these conditions may be different types of the same disorder.
Brugada syndrome affects both men and women, but occurs more often in men. The incidence rate is currently unknown due to its recent identification and discovery. It is estimated to affect 5 out of every 10,000 people. Brugada syndrome occurs worldwide, but is seen more frequently in individuals of Southeast Asia and Japan. According to the medical literature, Brugada syndrome may account for 4 to 12 percent of all sudden deaths and 20 percent of all sudden deaths in individuals with structurally normal hearts.
Brugada syndrome may affect individuals of any age, but symptoms most often occur in middle-aged men around the age of 40. The disorder was first described in the medical literature in 1992.
Symptoms of the following disorders can be similar to those of Brugada syndrome. Comparisons may be useful for a differential diagnosis:
Romano-Ward syndrome is an inherited heart (cardiac) disorder characterized by abnormalities affecting the electrical system of the heart. The severity of Romano-Ward syndrome varies greatly from case to case. Some individuals may have no apparent symptoms (asymptomatic); others may develop abnormally increased heartbeats (tachyarrhythmias) resulting in episodes of unconsciousness (syncope), cardiac arrest, and potentially sudden death. Romano-Ward syndrome is inherited as an autosomal dominant trait. One type of Romano-Ward syndrome called long QT syndrome type 3 (LQT3) is caused by abnormalities in the SCN5A gene; therefore, LQT3 and Brugada syndrome may be different types of the same disorder. (For more information on this disorder, choose Romano-Ward as your search term in the Rare Disease Database.)
Arrhythmogenic right ventricular dysplasia (ARVC) is a rare form of non-ischemic cardiomyopathy in which the normal muscular tissue of the right ventricle is replaced by fatty tissue. The symptoms of ARVD vary greatly. Symptoms may develop during childhood, but in most cases do not appear until the 30s or 40s. Symptoms associated with ARVD may include irregular heartbeats (arrhythmias), shortness of breath, swollen neck veins, abdominal discomfort, and fainting episodes (syncope). In some cases, no symptoms are apparent until an affected individual goes into cardiac arrest and possibly sudden death. (For more information on this disorder, choose arrhythmogenic right ventricular dysplasia as your search term in the Rare Disease Database.)
Duchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. It is usually recognized between three and six years of age. DMD is characterized by weakness and wasting (atrophy) of the muscles of the pelvic area followed by the involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles of the body. The disease is progressive and most affected individuals require a wheelchair by the teenage years. Serious life-threatening complications may ultimately develop including disease of the heart muscle (cardiomyopathy) and breathing (respiratory) difficulties. DMD is caused by changes (mutations) of the DMD gene on the X chromosome. The gene regulates the production of a protein called dystrophin that is found in association with the inner side of the membrane of skeletal and cardiac muscle cells. Dystrophin is thought to play an important role in maintaining the structure of these muscle cells.
Additional disorders may have similar heart rhythm abnormalities as those seen in Brugada syndrome. These disorders include acute myocarditis, acute pulmonary thromboemboli, right ventricular ischemia or infarction, thiamine deficiency, hypercalcemia and hyperkalemia.
The diagnosis of Brugada syndrome is based on a thorough clinical evaluation, a complete medical and family history that may include a family history of sudden cardiac death, and a specialized test known as an electrocardiogram (ECG of EKG) that records electrical activity of the heart and may reveal abnormal electrical patterns. Physicians may use specific drugs (sodium channel blockers) that provoke characteristic EKG features of Brugada syndrome.
Molecular genetic (DNA) testing is available for mutations in all eight genes to confirm the diagnosis but only about 20-25% of affected individuals have an identifiable gene mutation. Sequence analysis of the SCN5A gene is the first step in making a molecular genetic diagnosis because mutations in this gene are the most common cause of Brugada syndrome.
Clinical Testing and Work-Up
An electrocardiogram is recommended to determine the extent of disease in those affected. An electrophysiologic study may be used to assess risk of sudden cardiac death.
No cure for Brugada syndrome exists. Individuals at a high risk of ventricular fibrillation are treated with an implantable cardioverter defibrillator (ICD). This device detects the abnormal heartbeat automatically and selectively delivers an electrical impulse to the heart restoring normally rhythm.
Isoproterenol is an antiarrhythmic, which is used an effective way to respond to electrical storms (unstable ventricular arrhythmias). Recommendations for treatment of asymptomatic individuals is controversial. Possible treatments may include: observation until symptoms develop, although the first symptom is sometimes sudden cardiac death, or the use of family history or electrophysiologic study to determine who is appropriate for ICD placement.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Brugada Syndrome 1; BRGDA1. Entry No: 601144. Last Edited December 20, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed:February 5, 2013.
Report last updated: 2013/02/07 00:00:00 GMT+0