Brugada syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]
Overview
Approximately 20% of persons with Brugada syndome have a mutation in the gene SCN5A. This gene encodes for the sodium ion channel. The mutation is inherited in an autosomal dominant pattern, and is more commonly seen in males. Brugada syndrome has also been shown to result from defects in a calcium channel.
Pathophysiology
- 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).[1]
- 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.[2]
| Type | OMIM | Mutation | Notes |
| B1 | 601144 | alpha subunit of the sodium channel (SCN5A) | Current through this channel is commonly referred to as INa. Gain of this channel leads to an unopposed Ito current (KCND2) |
| B2 | 611778 | GPD1L, Glycerol-3-phosphate dehydrogenase like peptide | |
| B3 | 114205 | CACNA1C | Alpha subunit of cardiac L-type calcium channel.[3] |
| B4 | 600003 | CACNB2 | Beta-2 subunit of the voltage dependent L-type calcium channel.[3] |
| B5 | 604433 | KCNE3 which coassembles with KCND3 | Beta subunit to KCND3. Modulates the Ito potassium outward current[4] |
| B6 | 600235 | SCN1B | Beta-1 subunit of the sodium channel SCN5A[5] |
- 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. [6]
- 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).[7]
- 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.[8] [9] [10] [11] [12] [13] [14]
- SCN5A is a gene that encodes the alpha sodium unit of the cardiac sodium channel. Mutations in SCN5A account for about 15-30% of Brugada syndrome cases. A negative genetic test for SCN5A does not exclude that SCN5A is causing the clinical syndrome because the genetic tests do not evaluate for mutations in promotors, cryptic splicing mutations, or gross rearrangements in the protein product.[15]
- Glycerol-3-phosphate dehydrogenase (GPD1L) is associated with progressive conduction disease and low sensitivity to procainamide resulting from decreased Isodium current. It has a relatively good prognosis.
- CACNA1C (alpha subunit of L-type cardiac calcium channel) and CACNB2b (beta subunit of L-type cardiac calcium channel) is associated with a shortened QT interval and a combinatin Brugada/Short QT interval syndrome.
References
- ↑ Lehnart, Stephan E.; Ackerman, Michael J.; Benson, D. Woodrow; Brugada, Ramon; Clancy, Colleen E.; Donahue, J. Kevin; George, Alfred L.; Grant, Augustus O.; Groft, Stephen C.; January, Craig T.; Lathrop, David A.; Lederer, W. Jonathan; Makielski, Jonathan C.; Mohler, Peter J.; Moss, Arthur; Nerbonne, Jeanne M.; Olson, Timothy M.; Przywara, Dennis A.; Towbin, Jeffrey A.; Wang, Lan-Hsiang; Marks, Andrew R. (2007). "Inherited Arrhythmias". Circulation. 116 (20): 2325–2345. doi:10.1161/CIRCULATIONAHA.107.711689. ISSN 0009-7322.
- ↑ Delpón, Eva; Cordeiro, Jonathan M.; Núñez, Lucía; Thomsen, Poul Erik Bloch; Guerchicoff, Alejandra; Pollevick, Guido D.; Wu, Yuesheng; Kanters, J�rgen K.; Larsen, Carsten Toftager; Hofman-Bang, Jacob; Burashnikov, Elena; Christiansen, Michael; Antzelevitch, Charles (2008). "Functional Effects of
KCNE3
Mutation and Its Role in the Development of Brugada Syndrome". Circulation: Arrhythmia and Electrophysiology. 1 (3): 209–218. doi:10.1161/CIRCEP.107.748103. ISSN 1941-3149. replacement character in
|first8=at position 2 (help); line feed character in|title=at position 22 (help) - ↑ 3.0 3.1 Antzelevitch C, Pollevick GD, Cordeiro JM; et al. (2007). "Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death". Circulation. 115 (4): 442–229. doi:10.1161/CIRCULATIONAHA.106.668392. PMID 17224476.
- ↑ Delpon E, Cordeiro JM, Núñez L; et al. (2008). "Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome". Circulation Arrhythmia and Electrophysiology. 1 (3): 209–18. doi:10.1161/CIRCEP.107.748103. PMID 19122847.
- ↑ Watanabe H, Koopmann TT, Le Scouarnec S; et al. (2008). "Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans". J. Clin. Invest. 118 (6): 2260–8. doi:10.1172/JCI33891. PMC 2373423. PMID 18464934. Unknown parameter
|month=ignored (help) - ↑ Napolitano C, Priori SG (2006). "Brugada syndrome". Orphanet journal of rare diseases. 1: 35. doi:10.1186/1750-1172-1-35. PMID 16972995.
- ↑ Antzelevitch C (2007). "Genetic basis of Brugada syndrome". Heart rhythm : the official journal of the Heart Rhythm Society. 4 (6): 756–7. doi:10.1016/j.hrthm.2007.03.015. PMID 17556198.
- ↑ Brugada Syndrome. Charles Antzelevitch, PH.D. PACE 2006; 29:1130–1159
- ↑ Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome: A multicenter report. J Am Coll Cardiol 1992; 20:1391–1396.
- ↑ Antzelevitch C, Brugada P, Brugada J, Brugada R, Shimizu W, Gussak I, Perez Riera AR. Brugada syndrome. A decade of progress. Circ Res 2002; 91:1114–1119.
- ↑ Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: Consensus report. Eur Heart J 2002; 23:1648–1654.
- ↑ Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: Consensus report. Circulation 2002; 106:2514–2519.
- ↑ Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome. Report of the second consensus conference. Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005; 111:659–670.
- ↑ Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome:Report of the second consensus conference. Heart Rhythm 2005; 2:429–440.
- ↑ Juang, Jyh-Ming Jimmy; Horie, Minoru (2016). "Genetics of Brugada syndrome". Journal of Arrhythmia. 32 (5): 418–425. doi:10.1016/j.joa.2016.07.012. ISSN 1880-4276.