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基因變異性心律不整--Brugada 症候群
台大醫院 莊志明
突發心因性猝死 (Sudden cardiac death) 在西方國家一直是死亡原因的主因
之一,發生率約每年每 1000 人就有一個人死於突發心因性猝死症,而在自然死
亡中有大於四分之一是突然猝死,而這突發性猝死中,大部分都和心肌缺氧或心
臟結構異常有關;但 Autopsy 中卻發現有將近 10~20%的人沒有特殊心臟結構異
常 1
。
在西元 1992 年,Brugada 兄弟報告有 8 個病人之前心臟沒有特別的疾病,
如冠狀動脈疾病或心肌症等,卻發生了致命性的猝死;這些人的心電圖有異於常
人之特殊變化,為右束枝傳導阻滯 (Right Bundle Branch Block)及在前胸導極
V1、V2 及 V3 有 ST 節段上升 (ST segment elevation) 2
。
臨床上,這些人大多會以反覆昏厥 (repeated syncope)、抽搐 (seizure)、或突然猝
死 (cardiac arrest) 表現,好發在清晨睡覺的時候,主要的發病年齡為約 40 歲,
尤其是在男性,在發病之前並不會有特殊的前驅症狀,也都沒有特殊的心血管疾
病,另外這個疾病有部分的遺傳傾向,所以有些人有家族史。
病人送至醫院時,常見以心室性顫動 (Ventricular Fibrillation) 或多型性心室
過速 (Polymorphic Ventricular Tachycardia) 表現 3
;有些人來得及送醫,則可能
經急救而挽回生命,若發生太久心室性過速心率不整 (Ventricular
tachyarrhythmia),則會死亡,但這種心律不整有時是一過性的(transient),所以有
些人會以反覆昏厥表現,送至醫院時,心電圖不一定能見到 Brugada Type 之心電
圖變化,可能是正常心電圖,也因此為何這些年輕人不明原因突然猝死,到了西
元 1992 年才由 Brugada 兄弟找出部分原因,命名為 Brugada Syndrome;至此之
後,全世界各國陸續發表這個疾病,包括歐洲、美洲、亞洲、澳洲等,流行病學
亦發現,Brugada 症候群是小於 50 歲的亞洲男性自然死亡的主因 1
,日本、泰國、
新加坡、寮國、柬埔寨、越南及印尼都有病例報告,但卻鮮少中國人之病例 3, 4
。
自從 Brugada 症候群在西元 1992 年發表後,醫學界即快速地利用現代高
科技的分子生物技術及遺傳基因分析,探討有關 Brugada 症候群的致病機轉;
西元 1998 年,發表在 Nature 的論文證明,某些 Brugada 症候群是由於位在第
3 對染色體的心臟鈉離子通道基因(Cardiac sodium channel gene, SCN5A) 突變
所造成的 5
。而目前 SCN5A 基因突變有三種型式;1.splice-donor 2.frame-shift
3.missense5, 6
;不論那一型突變,都會造成 fast sodium channel current 減少,間
接造成 epicardium 和 endocardium 之間動作電位(action potential)的
heterogenicity,而引起 phase2 re-entry 和 ventricular fibrillation7-10
;SCN5A 這個
基因只有人的心臟會表現,並不會在肝臟、骨骼肌或子宮表現 6, 11
,大小約 80
kb,含 28 個 exons,所形成的蛋白含 2016 個胺基酸,這個蛋白形成了鈉離子
通道的 α-次單位,而 α-次單位包括了四個大區塊(DI-DIV),每一個大區塊含有
6 個橫跨細胞膜的小區塊所組成,如圖一。而在過去四年,全世界各地陸陸續
續都發現了 SCN5A 上不同的突變點,已多達約一百個。但 Brugada 症候群的
病人中,仍有 75%~80%的病人在 SCN5A 找不到致病基因。
從 2000 年開始,我們陸續收集台大醫院 Brugada Syndrome 病人的臨床資
料,而台灣其它的醫學中心和醫院,也會轉送 Brugada Syndrome 患者來本醫院
治療,或進行基因突變鑑定分析。在各醫院的全力支持下,我們收集了全台灣有
關 Brugada Syndrome 的臨床資料及 DNA 檢體。根據國外報告,SCN5A 基因目前
被證實為 Brugada syndrome 的主要致病基因,在白人族群裡, 20-25%的這類病
人是由於 SCN5A 基因突變引起的,所以過去十年裡,我們專注於分析 SCN5A 突變。
雖然我們已經找出台灣漢人數個獨特的 SCN5A 基因突變,但卻少於 15%的台灣
Brugada Syndrome 病人有 SCN5A 突變,意味著台灣 Brugada Syndrome 患者帶有
其它基因突變的可能性。這些基因包含了 CACNA1C、CACNB2、SCN1B、KCNE3、SCN3B
最近被指出與 Brugada Syndrome 有相關,
另外,有 15%的病人沒有家族史,這些人可能是 sporadic mutations。除此之
外,發現 Brugada 症候群病人的家族成員有四分之一會帶有這個異常的基因,
但卻有不同程度的表現 12
;另一方面,Brugada 症候群病人的子女會有將近二分
之一的機會得到這疾病,因此病人的親屬都應接受篩檢。
1. Brugada P, Brugada R, Brugada J. The brugada syndrome. Current Cardiology
Reports. 2000;2:507-514
2. 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
3. A. John Camm, Charles Antzelevitch, Brugada. P. Clinical approaches to
tachyarrhythmias volumn 10 the brugada syndrome. NY: Futura Publishing
Company; 1999.
4. K. T. Goh, T. C. Chao, Chew. CH. Sudden noctural deaths among thai
construction workers in singapore. The Lancet. 1990: May 12;1154
5. Chen Q, Kirsch GE, Zhang D, et, al. Genetic basis and molecular mechanisms
for idiopathic ventricular fibrillation. Nature. 1998;392:293-295
6. Wang Q, Shen J, Splawski I, et, al. Scn5a mutations associated with an
inherited cardiac arrhythmia, long qt syndrome. Cell. 1995;80:805
7. Antzelevitch C. The brugada syndrome. J Cardiovasc Electrophysiol.
1998;9:513-516
8. Yan GX, Antzelevitch C. Cellular basis for the brugada syndrome and other
mechanisms of arrhythmogenesis associated with st segment elevation.
Circulation. 1999;100:1660-1666
9. Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV,
Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the
electrocardiographic phenotype of the brugada syndrome are temperature
dependent. Circ Res. 1999;85:803-809
10. Deschenes I, Baroudi G, Berthet M, Barde I, Chalvidan T, Denjoy I,
Guicheney P, Chahine M. Electrophysiological characterization of scn5a
mutations causing long qt (e1784k) and brugada (r1512w and r1432g)
syndromes. Cardiovasc Res. 2000;46:55-65
11. Wang Q, Shen J, Li Z, et, al. Cardiac sodium channel mutations in patients
with long qt syndrome, an inherited cardiac arrhythmia. Hum Mol Genet.
1995;4:1603
12. Marco Alings, Arthur Wilde. "Brugada" syndrome clinical data and suggested
pathophysiological mechanism. Circulation. 1999;99:666-673

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基因變異性心律不整Brugada 症候群-莊志明

  • 1. 基因變異性心律不整--Brugada 症候群 台大醫院 莊志明 突發心因性猝死 (Sudden cardiac death) 在西方國家一直是死亡原因的主因 之一,發生率約每年每 1000 人就有一個人死於突發心因性猝死症,而在自然死 亡中有大於四分之一是突然猝死,而這突發性猝死中,大部分都和心肌缺氧或心 臟結構異常有關;但 Autopsy 中卻發現有將近 10~20%的人沒有特殊心臟結構異 常 1 。 在西元 1992 年,Brugada 兄弟報告有 8 個病人之前心臟沒有特別的疾病, 如冠狀動脈疾病或心肌症等,卻發生了致命性的猝死;這些人的心電圖有異於常 人之特殊變化,為右束枝傳導阻滯 (Right Bundle Branch Block)及在前胸導極 V1、V2 及 V3 有 ST 節段上升 (ST segment elevation) 2 。 臨床上,這些人大多會以反覆昏厥 (repeated syncope)、抽搐 (seizure)、或突然猝 死 (cardiac arrest) 表現,好發在清晨睡覺的時候,主要的發病年齡為約 40 歲, 尤其是在男性,在發病之前並不會有特殊的前驅症狀,也都沒有特殊的心血管疾 病,另外這個疾病有部分的遺傳傾向,所以有些人有家族史。 病人送至醫院時,常見以心室性顫動 (Ventricular Fibrillation) 或多型性心室 過速 (Polymorphic Ventricular Tachycardia) 表現 3 ;有些人來得及送醫,則可能 經急救而挽回生命,若發生太久心室性過速心率不整 (Ventricular tachyarrhythmia),則會死亡,但這種心律不整有時是一過性的(transient),所以有 些人會以反覆昏厥表現,送至醫院時,心電圖不一定能見到 Brugada Type 之心電 圖變化,可能是正常心電圖,也因此為何這些年輕人不明原因突然猝死,到了西 元 1992 年才由 Brugada 兄弟找出部分原因,命名為 Brugada Syndrome;至此之 後,全世界各國陸續發表這個疾病,包括歐洲、美洲、亞洲、澳洲等,流行病學 亦發現,Brugada 症候群是小於 50 歲的亞洲男性自然死亡的主因 1 ,日本、泰國、 新加坡、寮國、柬埔寨、越南及印尼都有病例報告,但卻鮮少中國人之病例 3, 4 。 自從 Brugada 症候群在西元 1992 年發表後,醫學界即快速地利用現代高 科技的分子生物技術及遺傳基因分析,探討有關 Brugada 症候群的致病機轉; 西元 1998 年,發表在 Nature 的論文證明,某些 Brugada 症候群是由於位在第 3 對染色體的心臟鈉離子通道基因(Cardiac sodium channel gene, SCN5A) 突變 所造成的 5 。而目前 SCN5A 基因突變有三種型式;1.splice-donor 2.frame-shift 3.missense5, 6 ;不論那一型突變,都會造成 fast sodium channel current 減少,間 接造成 epicardium 和 endocardium 之間動作電位(action potential)的 heterogenicity,而引起 phase2 re-entry 和 ventricular fibrillation7-10 ;SCN5A 這個 基因只有人的心臟會表現,並不會在肝臟、骨骼肌或子宮表現 6, 11 ,大小約 80 kb,含 28 個 exons,所形成的蛋白含 2016 個胺基酸,這個蛋白形成了鈉離子 通道的 α-次單位,而 α-次單位包括了四個大區塊(DI-DIV),每一個大區塊含有 6 個橫跨細胞膜的小區塊所組成,如圖一。而在過去四年,全世界各地陸陸續
  • 2. 續都發現了 SCN5A 上不同的突變點,已多達約一百個。但 Brugada 症候群的 病人中,仍有 75%~80%的病人在 SCN5A 找不到致病基因。 從 2000 年開始,我們陸續收集台大醫院 Brugada Syndrome 病人的臨床資 料,而台灣其它的醫學中心和醫院,也會轉送 Brugada Syndrome 患者來本醫院 治療,或進行基因突變鑑定分析。在各醫院的全力支持下,我們收集了全台灣有 關 Brugada Syndrome 的臨床資料及 DNA 檢體。根據國外報告,SCN5A 基因目前 被證實為 Brugada syndrome 的主要致病基因,在白人族群裡, 20-25%的這類病 人是由於 SCN5A 基因突變引起的,所以過去十年裡,我們專注於分析 SCN5A 突變。 雖然我們已經找出台灣漢人數個獨特的 SCN5A 基因突變,但卻少於 15%的台灣 Brugada Syndrome 病人有 SCN5A 突變,意味著台灣 Brugada Syndrome 患者帶有 其它基因突變的可能性。這些基因包含了 CACNA1C、CACNB2、SCN1B、KCNE3、SCN3B 最近被指出與 Brugada Syndrome 有相關, 另外,有 15%的病人沒有家族史,這些人可能是 sporadic mutations。除此之 外,發現 Brugada 症候群病人的家族成員有四分之一會帶有這個異常的基因, 但卻有不同程度的表現 12 ;另一方面,Brugada 症候群病人的子女會有將近二分 之一的機會得到這疾病,因此病人的親屬都應接受篩檢。 1. Brugada P, Brugada R, Brugada J. The brugada syndrome. Current Cardiology Reports. 2000;2:507-514 2. 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 3. A. John Camm, Charles Antzelevitch, Brugada. P. Clinical approaches to tachyarrhythmias volumn 10 the brugada syndrome. NY: Futura Publishing Company; 1999. 4. K. T. Goh, T. C. Chao, Chew. CH. Sudden noctural deaths among thai construction workers in singapore. The Lancet. 1990: May 12;1154 5. Chen Q, Kirsch GE, Zhang D, et, al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature. 1998;392:293-295 6. Wang Q, Shen J, Splawski I, et, al. Scn5a mutations associated with an inherited cardiac arrhythmia, long qt syndrome. Cell. 1995;80:805 7. Antzelevitch C. The brugada syndrome. J Cardiovasc Electrophysiol. 1998;9:513-516 8. Yan GX, Antzelevitch C. Cellular basis for the brugada syndrome and other mechanisms of arrhythmogenesis associated with st segment elevation. Circulation. 1999;100:1660-1666 9. Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV,
  • 3. Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic phenotype of the brugada syndrome are temperature dependent. Circ Res. 1999;85:803-809 10. Deschenes I, Baroudi G, Berthet M, Barde I, Chalvidan T, Denjoy I, Guicheney P, Chahine M. Electrophysiological characterization of scn5a mutations causing long qt (e1784k) and brugada (r1512w and r1432g) syndromes. Cardiovasc Res. 2000;46:55-65 11. Wang Q, Shen J, Li Z, et, al. Cardiac sodium channel mutations in patients with long qt syndrome, an inherited cardiac arrhythmia. Hum Mol Genet. 1995;4:1603 12. Marco Alings, Arthur Wilde. "Brugada" syndrome clinical data and suggested pathophysiological mechanism. Circulation. 1999;99:666-673