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The Brugada syndrome is a genetic disease that is characterised by abnormal electrocardiogram (ECG) findings and an increased risk of sudden cardiac death. It is also known as Sudden Unexpected Death Syndrome[1] (SUDS), and is the most common cause of sudden death in young men without known underlying cardiac disease in Thailand and Laos[2].
Although the ECG findings of Brugada syndrome were first reported[3] among survivors of cardiac arrest in 1989, it was only in 1992 that the Brugada brothers[4] recognised it as a distinct clinical entity, causing sudden death by causing ventricular fibrillation (a lethal arrhythmia) in the heart.
Approximately 20% of the cases of Brugada syndrome have been shown to be associated with mutation(s) in the gene that encodes for the sodium ion channel in the cell membranes of the muscle cells of the heart (the myocytes). The gene, named SCN5A, is located on the short arm of the third chromosome (3p21). Loss-of-function mutations in this gene lead to a loss of the action potential dome of some epicardial areas of the right ventricle. This results in transmural and epicardial dispersion of repolarization. The transmural dispersion underlies ST-segment elevation and the development of a vulnerable window across the ventricular wall, whereas the epicardial dispersion of repolarization facilitates the development of phase 2 reentry, which generates a phase 2 reentrant extrasystole that captures the vulnerable window to precipitate ventricular tachycardia and/or fibrillation that often results in sudden cardiac death. At present time however, all the reported patients died because of the disease and submitted to detailed necropsy study, have shown a structural right ventricular pathology underlying the syndrome.
Over 160 mutations in the SCN5A gene have been discovered to date, each having varying mechanisms and effects on function, thereby explaining the varying degrees of penetration and expression of this disorder. [7]
An example of one of the mechanisms in which a loss of function of the sodium channel occurs is a mutation in the gene that disrupts the sodium channel’s ability to bind properly to ankyrin-G, an important protein mediating interaction between ion channels and cytoskeletal elements. Very recently a mutation in a second gene, Glycerol-3-phosphate dehydrogenase 1-like gene (GPD1L) has been shown to result in Brugada Syndrome in a large multigenerational family (London, 2006). This gene acts as an ion channel modulator in the heart, although the exact mechanism is not yet understood.
Recently Antzelevitch has identified mutations in the L-type calcium channel subunits (CACNA1C (A39V and G490R) and CACNB2 (S481L)) leading to ST elevation and a relatively short QT interval (below 360 msec).[8]
This condition is inherited in an autosomal dominant pattern and is more common in males. In addition it has a higher prevalence in most Asian populations.
Genetic testing for Brugada syndrome is clinically available and may help confirm a diagnosis in patients suspected of having Brugada syndrome, as well as differentiate between relatives who are at-risk for the disease and those who are not (Overview of Brugada Syndrome Genetic Testing).
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