Hong Kui, Berruezo-Sanchez Antonio, Poungvarin Naravat, Oliva Antonio, Vatta Matteo, Brugada Josep, Brugada Pedro, Towbin Jeffrey A, Dumaine Robert, Piñero-Galvez Carlos, Antzelevitch Charles, Brugada Ramon
Molecular Genetics Program, Masonic Medical Research Laboratory, Utica, New York 13501, USA.
J Cardiovasc Electrophysiol. 2004 Jan;15(1):64-9. doi: 10.1046/j.1540-8167.2004.03341.x.
Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V(1) to V(3) of patients with structurally normal hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in SCN5A.
We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in SCN5A. The R367H mutation failed to generate any current when heterologously expressed in HEK cells.
Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false-positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome.
Brugada综合征的特征是结构正常的心脏患者因恶性心律失常继发猝死，且心电图V(1)至V(3)导联出现ST段抬高。这种心电图模式常被隐匿，但可通过使用强效钠通道阻滞剂使其显现。与先天性3型长QT综合征（LQT3）和意外猝死综合征一样，Brugada综合征与SCN5A基因突变有关。
我们对一个患有Brugada综合征的大型欧洲家族进行了筛查。三名成员（两名女性）曾发生恶性室性心律失常。十名成员在基线时显示出Brugada综合征特征性的心电图模式，八名成员仅在服用阿义马林后才显示出该模式（总共12名女性）。单倍型分析显示，所有基线心电图阳性的个体均共享SCN5A基因座。SCN5A测序鉴定出一个错义突变R367H，该突变先前与意外猝死综合征相关。八名服用阿义马林后心电图呈阳性但之前未呈阳性的个体中，有两名没有R367H突变，测序分析也未在SCN5A中发现任何其他突变。R367H突变在HEK细胞中异源表达时未能产生任何电流。
我们的结果支持以下假设：（1）意外猝死综合征和Brugada综合征是同一种疾病；（2）在意外猝死综合征中观察到的表型男性占优势不适用于这个家族，这表明除特定突变外的其他因素决定了性别差异；（3）阿义马林可能会提供假阳性结果。这些发现对Brugada综合征患者家庭成员的诊断和风险分层具有广泛意义。
