The first gene responsible for the disease was identified in 1998 by Chen and coworkers.[13] This gene, the a-subunit of the cardiac sodium channel gene, SCN5A, is responsible for the phase 0 of the cardiac action potential. The identification of mutations in SCN5A causing the disease and the decrease in availability of sodium ions indicates that a shift in the ionic balance in favor of Ito during phase 1 of the action potential is the determinant of the disease.[7] To date, this is the only gene linked to Brugada syndrome. SCN5A has been identified in approximately 25% of the patients with Brugada syndrome, indicating there is at least another gene responsible for the disease. In 2002, a second locus on chromosome 3 was identified, although the gene responsible has not been identified.[14] Close to 60 different mutations in SCN5A have been reported to date and approximately half of them have been biophysically characterized. The common denominator in the analysis of the mutations is the decrease in Na current availability by two main mechanisms: lack of expression of the mutant channel, or acceleration of inactivation of the channel.[15] In the case of T1620M mutation, the alteration in the ionic currents worsened at higher temperatures.[16] This has clinical significance as several cases of ventricular fibrillation in patients with Brugada syndrome have been precipitated during febrile states.[17-19]

Brugada syndrome is inherited as an autosomal dominant disorder and usually the disease manifests itself in individuals at risk in their 40s. However, it has also been described as causing sudden infant death syndrome (SIDS).[20] In addition to Brugada syndrome, mutations of SCN5A can lead to a large spectrum of phenotypes, including long-QT syndrome (LQT3),[21] isolated progressive cardiac conduction defect,[22] idiopathic ventricular fibrillation,[13] and sudden unexplained nocturnal death syndrome (SUDS or SUNDS).[23] These are all considered allelic diseases, caused by mutations in the same gene. Electrocardiographic, clinical, and biophysical data have clarified the relationship between these diseases in part.

When comparing to LQT3, Brugada syndrome could be considered a mirror image. Biophysical data indicate that LQT3 mutations cause a delayed inactivation of the channel,[21] which is exactly the opposite to Brugada syndrome, where there is an accelerated inactivation.[16] The difference between the two diseases is, however, difficult to identify in some cases, and one family was described manifesting the phenotype of both Brugada and long-QT syndromes.[24] Likewise, the line between progressive conduction disease and Brugada syndrome is closer than ever after the publication of a paper with a family displaying both diseases.[25] Whether they represent variable phenotypic expression of the same disease is difficult to ascertain. All affected family members in this family, with Brugada syndrome or conduction disease, had a mutation that proved lethal to some of its members. This certainly raises important issues regarding therapy, prevention, and risk stratification.

Recent studies have shed some light on the distinctions or lack thereof between Brugada syndrome and sudden unexpected death syndrome (SUDS) in Southeast Asia. Sudden unexpected death syndrome is very prevalent in Southeast Asia. In countries such as Thailand, it is believed to affect up to 1% of the population, and it is the most common cause of death in young males, second only to car accidents.[26] The patients commonly die at night and the male-to-female ratio is on the order of 10:1. Electrocardiographically, the disease is identical to Brugada syndrome. It is also caused by mutations in SCN5A and biophysical data indicate a nonworking SCN5A or accelerated inactivation.[23] These characteristics are similar to those of the Brugada syndrome, indicating they are the same disease.

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