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 syndrome 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

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]
  • 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]
  1. 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]
  2. Glycerol-3-phosphate dehydrogenase (GPD1L) is associated with progressive conduction disease and low sensitivity to procainamide resulting from decreased sodium current. It has a relatively good prognosis.
  3. 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

  1. 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.
  2. 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. 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.
  4. 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.
  5. 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)
  6. Napolitano C, Priori SG (2006). "Brugada syndrome". Orphanet journal of rare diseases. 1: 35. doi:10.1186/1750-1172-1-35. PMID 16972995.
  7. 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.
  8. Brugada Syndrome. Charles Antzelevitch, PH.D. PACE 2006; 29:1130–1159
  9. 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.
  10. 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.
  11. Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: Consensus report. Eur Heart J 2002; 23:1648–1654.
  12. Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: Consensus report. Circulation 2002; 106:2514–2519.
  13. 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.
  14. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome:Report of the second consensus conference. Heart Rhythm 2005; 2:429–440.
  15. 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.

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