NORD gratefully acknowledges 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. Recent reports suggest that Brugada syndrome could be responsible up to 20% of sudden death in patients with structurally normal hearts. The clinical phenotype manifests in adulthood, and it is more frequent in males. Frequently, sudden death can be the first manifestation of the disease. Brugada syndrome is a genetic disease and follows autosomal dominant inheritance. Currently, the prevalence of Brugada syndrome is estimated at 5 in 10,000 people.
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. The genetic basis of Brugada syndrome was established by Ramon Brugada in 1998.
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 person to person. 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 mutations in the SCN5A gene which encodes the α-subunit of the voltage-gated Nav1.5, the cardiac sodium channel responsible for regulating rapid sodium current –INa-. It induces 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.
Currently, more than 250 mutations associated with BrS have been reported in 18 different genes (SCN5A, SCN1B, SCN2B, SCN3B, SCN10A, ABCC9, GPD1L, CACNA1C, CACNB2, CACNA2D1, KCND3, KCNE3, KCNE1L -KCNE5-, KCNJ8, HCN4, RANGRF, SLMAP, and TRPM4), which encode for sodium, potassium, and calcium channels or proteins associated with these channels. Despite the identification of 18 associated genes, 65%–70% of clinically diagnosed cases remain without an identifiable genetic cause.
Most part of these mutations is 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. The 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 (5-8 times more). 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 up to 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.
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 genes to confirm the diagnosis but only about 30-35% of affected individuals have an identifiable gene mutation after a comprehensive genetic test. 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 (nearly 25%).
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, so far. 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 are 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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Contact for more information about Brugada syndrome:
Cardiovascular Genetics Center, Gencardio
Institut Investigació Biomèdica de Girona (IDIBGI)
C/ Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2)
17290, Salt, Girona (Spain)
Email: [email protected]
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