SUDDEN UNEXPLAINED NOCTURNAL DEATH SYNDROME
BRGDA1
SUNDS CARDIAC CONDUCTION DEFECT, NONSPECIFIC, INCLUDED
RIGHT BUNDLE BRANCH BLOCK, ST SEGMENT ELEVATION, AND SUDDEN DEATH SYNDROME
Brugada syndrome is characterized by an ST-segment elevation in the right precordial electrocardiogram leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests during adulthood, with ... Brugada syndrome is characterized by an ST-segment elevation in the right precordial electrocardiogram leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests during adulthood, with a mean age of sudden death of 41 +/- 15 years, but occurs in infants and children (summary by Antzelevitch et al., 2005). - Genetic Heterogeneity of Brugada Syndrome Brugada syndrome-2 (611777) is caused by mutation in the GPD1L gene (611778). Brugada syndrome-3 (611875) and Brugada syndrome-4 (611876), the phenotypes of which include a shortened QT interval on ECG, are caused by mutation in the CACNA1C (114205) and CACNB2 (600003) genes, respectively. Brugada syndrome-5 (612838) is caused by mutation in the SCN1B gene (600235). Brugada syndrome-6 (613119) is caused by mutation in the KCNE3 gene (604433). Brugada syndrome-7 (613120) is caused by mutation in the SCN3B gene (608214). Brugada syndrome-8 (613123) is caused by mutation in the HCN4 gene (605206).
Martini et al. (1989) described 6 patients with apparently idiopathic ventricular fibrillation, 3 of whom had a distinctive ECG pattern characterized by an upsloping ST segment in the right precordial leads ('early repolarization') in association with right bundle ... Martini et al. (1989) described 6 patients with apparently idiopathic ventricular fibrillation, 3 of whom had a distinctive ECG pattern characterized by an upsloping ST segment in the right precordial leads ('early repolarization') in association with right bundle branch block and T-wave inversion. In these patients, they documented subtle structural abnormalities of the right ventricle after detailed clinical investigation. Brugada and Brugada (1992) described 8 additional patients with the same ECG changes who experienced cardiac arrest due to ventricular fibrillation. They introduced the term 'right bundle branch block, ST segment elevation, and sudden death syndrome' to describe a seemingly new clinical entity. Brugada et al. (2001) discussed the prognostic value of electrophysiologic studies in Brugada syndrome. Alings and Wilde (1999) suggested that Brugada syndrome accounts for up to 40 to 60% of cases of ventricular fibrillation previously classified as idiopathic. In 5 to 10% of survivors of cardiac arrest due to ventricular arrhythmia, no cause, such as coronary artery disease or a structural abnormality of the heart, is found. There are no stringent diagnostic criteria for Brugada syndrome (Grace, 1999; Gussak et al., 1999). The electrocardiogram usually suggests the diagnosis; the pattern of the right precordial leads resembles those seen in right bundle branch block with variable ST segment elevation and a coved or saddle-type appearance. The ECG changes may not be apparent unless an agent that inhibits the cardiac sodium channel, such as flecainide or procainamide, is administered. Intravenous flecainide may be the drug of choice to be used as a diagnostic channel in patients presenting with a defect of ventricular fibrillation whose resting ECG is normal or in whom doubt about the diagnosis remains. Conversely, ST segment elevation may disappear after intravenous isoprenaline or exercise, whereas beta-blockade may exaggerate its appearance (Kasanuki et al., 1997). Alings and Wilde (1999) stated that only about 200 cases of Brugada syndrome had been reported. Over 90% of these cases had been in male patients, the mean age at first arrhythmic event ranging between 22 and 65 years. Brugada syndrome seems to be most prevalent in Southeast Asia and Japan (Wong et al., 1992; Nademanee et al., 1997). Symptoms occur mostly at night, and the folklore of many of these countries is replete with stories of young men with 'Lai Tai' (Thailand), 'Bangungut' (Philippines), or 'Pokkuri' (Japan), thrashing, screaming, and then dying suddenly in their beds. This disorder may be the leading cause of natural death among young men in the poverty-stricken northeast of Thailand. The annual mortality rate in this group was said by Nademanee et al. (1997) to be as high as 26-38 per 100,000. Priori et al. (2002) presented clinical data from 130 probands with Brugada syndrome and 70 affected family members. Overall, SCN5A mutations were identified in 28 probands; the remaining individuals fulfilled accepted diagnostic ECG criteria. Multivariate Cox regression analysis showed that, after adjusting for sex, a family history of sudden cardiac death, and mutation in SCN5A, the cooccurrence of spontaneous ST segment elevation in the anterior chest leads of a resting 12-lead ECG and a personal history of syncope identified persons at risk for cardiac arrest. The authors were unable to demonstrate a relationship between inducibility of arrhythmia during programmed electrical stimulation and subsequent spontaneous occurrence of ventricular fibrillation, suggesting that this clinical investigation was a poor predictor of cardiac risk. Further, Priori et al. (2002) suggested a risk stratification scheme designed to target the use of implantable cardioverter-defibrillator devices in patients with Brugada syndrome.
Screening of some families with the Brugada phenotype has revealed distinct mutations in the SCN5A gene (600163) which encodes the pore-forming alpha-subunit of the cardiac sodium channel (Chen et al., 1998). As pointed out by Rook et al. ... Screening of some families with the Brugada phenotype has revealed distinct mutations in the SCN5A gene (600163) which encodes the pore-forming alpha-subunit of the cardiac sodium channel (Chen et al., 1998). As pointed out by Rook et al. (1999), pharmacologic sodium channel blockade elicits or worsens the electrocardiographic features associated with Brugada syndrome, thus making SCN5A a plausible candidate gene. In patients with this syndrome, they found missense mutations in SCN5A and assessed the functional significance of these mutations by expression of the mutant sodium channel proteins in Xenopus oocytes. Significant effects on cardiac sodium channel characteristics were observed. Alterations seemed to be associated with an increase in inward sodium current during the action potential upstroke. Bezzina et al. (1999) presented a large, 8-generation Dutch family with a history of sudden death, most of which had occurred at night. One individual was thought to have died suddenly as the result of carotid sinus pressure while he was being shaved. Some living members of this family demonstrated ECG features compatible with Brugada syndrome and QT prolongation characteristic of long QT syndrome-3 (LQT3; 603830). SSCP analysis revealed an aberrant conformer corresponding to a novel mutation in the C terminal of the SCN5A protein (1795insD; 600163.0013). This family demonstrated that the long QT syndrome type-3 and Brugada syndrome appear to lie on a spectrum of cardiac electrophysiologic pathology caused by SCN5A mutation. Kyndt et al. (2001) reported a missense mutation (600163.0026) in the SCN5A gene in a large French family segregating both isolated cardiac conduction defect and Brugada syndrome in a dominant manner. In a patient with Brugada syndrome, Rivolta et al. (2001) identified a tyr1795-to-his mutation mutation in the SCN5A gene (Y1795H; 600163.0030). In a patient with Long QT syndrome-3, they identified a different mutation at the same codon (Y1795C; 600163.0029). They concluded that these findings provided further evidence of the close interrelationship between Brugada syndrome and long QT syndrome type 3 at the molecular level. Veldkamp et al. (2003) studied the effect of the 1795insD SCN5A mutation on sinoatrial (SA) pacemaking. Activity of 1795insD channels during SA node pacemaking was confirmed by action potential (AP) clamp experiments, and the previously characterized persistent inward current (I-pst) and negative shift were implemented into SA node (AP) models. The -10 mV shift decreased the sinus rate by decreasing the diastolic depolarization rate, whereas the I-pst decreased the sinus rate by AP prolongation, despite a concomitant increase in the diastolic depolarization rate. In combination, a moderate I-pst (1 to 2%) and the shift reduced the sinus rate by about 10%. Veldkamp et al. (2003) concluded that sodium channel mutations displaying an I-pst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients, whereas SA node pauses or arrest may result from failure of SA node cells to repolarize under conditions of extra net inward current. 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 to V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome. Vatta et al. (2002) found mutations in the SCN5A gene in 3 of 10 Asian SUNDS patients. In a sporadic Asian SUNDS patient, the authors identified a 1100G-A transition in SCN5A (600163.0021). The mutation is predicted to result in an arg367-to-his (R367H) substitution, which lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments. In transfected Xenopus oocytes, the R367H mutant channel did not express any current. The authors hypothesized that the likely effect of this mutation is to depress peak current due to the loss of one functional allele. Makita et al. (2008) studied 41 individuals from 15 LQT3 kindreds who carried the E1784K mutation in the SCN5A gene (600163.0008); the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome, and/or sinus node dysfunction (see 608567). In vitro functional characterization of E1784K compared to properties reported for other LQT3 variants suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block in response to Na channel blockers represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and Brugada syndromes, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors. Hedley et al. (2009) reviewed the diagnostic criteria for Brugada syndrome and the pathogenic mechanisms of mutations in the 7 genes known to date to cause disease. - Lidocaine-Induced Brugada Syndrome 1 In a 45-year-old black man with no history of cardiac disease who developed monomorphic wide-complex ventricular tachycardia with right precordial ST segment elevation after the administration of lidocaine, Barajas-Martinez et al. (2008) identified 2 mutations in the SCN5A gene, V232I and L1308F (600163.0040). A slight right precordial ST elevation remained 1 year after discontinuation of lidocaine. The patient's parents were unavailable for study, but given the severity of his clinical manifestations, the authors strongly suspected that both mutations were on the same allele (Dumaine, 2009). Using patch-clamp techniques in mammalian TSA201 cells, Barajas-Martinez et al. (2008) observed use-dependent inhibition of I(Na) by lidocaine that was more pronounced in double-mutant channels than in wildtype; the authors concluded that the double mutation in SCN5A alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes class IC characteristics with potent use-dependent block of the sodium channel. - Associations Pending Confirmation See 601327.0003 for discussion of a possible association between variation in the SCN2B gene and Brugada syndrome.