Brugada Syndrome

Excerpt

Clinical characteristics: Brugada syndrome is characterized by cardiac conduction abnormalities (ST segment abnormalities in leads V₁-V₃ on EKG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood, although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.

Diagnosis/testing: The diagnosis of Brugada syndrome is established clinically in an individual with characteristic EKG findings and suggestive clinical history and/or family history. A molecular diagnosis can be established in an individual with characteristic features and identification of a heterozygous pathogenic variant in SCN5A or one of the additional 42 genes associated with Brugada syndrome.

Management: Treatment of manifestations: Implantable cardioverter defibrillator (ICD) in individuals with a history of syncope or cardiac arrest; isoproterenol for electrical storms. During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by EKG.

Prevention of primary manifestations: Quinidine (1-2 g daily). Treatment of asymptomatic individuals is controversial.

Surveillance: EKG monitoring every one to two years for at-risk individuals with a family history of Brugada syndrome or who have a known pathogenic variant that can lead to Brugada syndrome.

Agents/circumstances to avoid: High fever, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic antagonists, tricyclic antidepressants; first-generation antihistamines (dimenhydrinate); cocaine; class 1C antiarrhythmic drugs (flecainide, propafenone) and class 1A agents (procainamide, disopyramide).

Evaluation of relatives at risk: Identification of relatives at risk using EKG or (if the pathogenic variant in the family is known) molecular genetic testing enables use of preventive measures and avoidance of medications that can induce ventricular arrhythmias.

Genetic counseling: In most instances Brugada syndrome is inherited in an autosomal dominant manner; the exception is KCNE5-related Brugada syndrome, which is inherited in an X-linked manner. Most individuals diagnosed with Brugada syndrome have an affected parent or another affected close relative. The proportion of individuals with Brugada syndrome caused by a de novo pathogenic variant is very low (~1%). Each child of an individual with autosomal dominant Brugada syndrome has a 50% chance of inheriting the pathogenic variant. The risk that a child will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors. Reduced penetrance and variable expressivity are hallmarks of Brugada syndrome. Once the Brugada syndrome-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Brugada syndrome are possible.