Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome

Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 03/2002; 11(3):337-45.
Source: PubMed


Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST-segment elevation in leads V1-V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome. We screened patients with SUNDS for mutations in SCN5A, the gene known to cause Brugada syndrome, as well as genes encoding ion channels associated with the long-QT syndrome. Ten families were enrolled, and screened for mutations using single-strand DNA conformation polymorphism analysis, denaturing high-performance liquid chromatography and DNA sequencing. Mutations were identified in SCN5A in three families. One mutation, R367H, lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A. A second mutation, A735V, lies in the first transmembrane segment of domain II (DIIS1) close to the first extracellular loop between DIIS1 and DIIS2, whereas the third mutation, R1192Q, lies in domain III. Analysis of these mutations in Xenopus oocytes showed that the R367H mutant channel did not express any current and the likely effect of this mutation is to depress peak current due to the loss of one functional allele. The A735V mutant expressed currents with steady state activation voltage shifted to more positive potentials. The R1192Q mutation accelerated the inactivation of the sodium channel current. Both mutations resulted in reduced sodium channel current (I(Na)) at a time corresponding to the end of phase 1 of the action potential, as described previously in the Brugada syndrome. Based upon these observations we suggest that SUNDS and Brugada syndrome are phenotypically, genetically and functionally the same disorder.

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    • "R1193Q has been implicated in both LQTs type 3, a gain of function disease,16 and in sudden unexplained nocturnal death syndrome, a loss of function disease.17 At the same time, R1193Q is considered as a polymorphism in Asians with an allele frequency of 8%.4,18 "
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    ABSTRACT: Long QT syndrome (LQTs) is an uncommon genetic disease causing sudden cardiac death with Torsade de Pointes (TdP). The first line drug treatment has been known to be β-blocker. We encountered a 15-year-old female student with LQTs who had prolonged QTc and multiple episodes of syncope or agonal respiration during sleep. Although her T wave morphology in surface electrocardiography resembled LQTs type 1, her clinical presentation was unusual. During the epinephrine test, TdP was aggravated during β-blocker medication, but alleviated by sodium channel blocker (mexiletine). Therefore, she underwent implantable cardioverter defibrillator implantation.
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    • "In the last decade of the past century, Josep and Pedro Brugada described eight patients with recurrent episodes of aborted sudden death, an electrocardiographic pattern characterized by a right bundle branch block and by a distinct coved-type ST-segment elevation in the right precordial leads V1–V3, but with no signs of structural heart disease [3] [4]. It was only in 2002 that the formerly called ''sudden unexpected nocturnal death syndrome (SUNDS),'' well known in southeast of Asia, was recognized as the same genetic and pathophysiologic condition of the BS [5]. The BS is a ''channellopathy'' typically associated with a high risk for SCD in young and otherwise healthy adults [6], in whom is responsible for 4–12% of all SCD. "
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    ABSTRACT: The Brugada Syndrome (BS) is a "channellopathy," characterized by ion (e.g., sodium, calcium, and potassium) channel dysfunction and typical ECG alterations, originally described by Osher and Wolff in 1953 and further elucidated by Josep and Pedro Brugada in 1991. BS is typically associated with a high risk for sudden cardiac death (SCD) in young and otherwise healthy adults. Although in several patients the heart is structurally normal, subtle structural abnormalities in the right ventricular outflow tract are increasingly been reported. The worldwide prevalence of this disorder is still uncertain, and there are some significant regional differences. The syndrome is characterized by a strong genetic basis, and several mutations have been identified in genes encoding subunits of cardiac sodium, potassium, and calcium channels, as well as in genes involved in the trafficking or regulation of these channels. Accordingly, eight types of BS (from BS1 to BS8) have already been described, involving mutations in SCN5A, GPD1-L, CACNA1c, CACNB2b, SCN1B, KCNE3, SCN3B, and HCN4 genes. The vast majority (i.e., up to two-third) of BS patients is asymptomatic, whereas the leading clinical manifestation is polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation (VF) and SCD. The diagnosis is still challenging, and ECG abnormalities represent one component of the diagnostic criteria which also include clinical and demographic data. Although molecular genetic testing is effective in detecting mutations in 20-38% of BS patients, it represents an appealing option for stratifying the risk of adverse events as well as for prenatal testing.
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    • "In general, LQT3 is caused by a gain of channel function while BrS is caused by a loss of channel function [6], [7]. Distinct cardiac phenotypes caused by SCN5A mutations have been described, including atrial fibrillation [8], sick sinus syndrome (SSS), conduction disorders such as atriventricular (AV)-block, and several more complex phenotypes [9]–[11], Dilated cardiomyopathy (DCM) is characterized by dilated cardiac chambers and reduced systolic function, which causes congestive heart failure. Patients with a family history of DCM account for approximately 20 to 25% of idiopathic DCM cases [12], [13]. "
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