Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.

Background-Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Methods and Results-We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals). Conclusions-KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.

Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

beta-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed beta-blockers, particularly in those who were symptomatic before starting this therapy.

Background-Although structural neuroimaging methods have been widely used to study brain morphology in schizophrenia, synthesizing this literature has been difficult. With the increasing popularity of voxel-based morphometric (VBM) methods where group differences are reported in standardized coordinates, it is possible to apply powerful meta-analytic techniques initially designed for functional neuroimaging. In the present manuscript, we perform a voxel-wise, coordinate-based meta-analysis to better conceptualize the neuroanatomic correlates of schizophrenia.

Background-The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite ␤-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. Methods and Results-We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543Ϯ65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with ␤-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (PϽ0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc Ͻ500 ms predicted very low risk. The percentage of patients with Ͼ5 CEs declined from 55% to 8% (PϽ0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (Pϭ0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. Conclusions-LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite ␤-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.

With the ever-increasing number of studies in human functional brain mapping, an abundance of data has been generated that is ready to be synthesized and modeled on a large scale. The BrainMap database archives peak coordinates from published neuroimaging studies, along with the corresponding metadata that summarize the experimental design. BrainMap was designed to facilitate quantitative meta-analysis of neuroimaging results reported in the literature and supports the use of the activation likelihood estimation (ALE) method. In this paper, we present a discussion of the potential analyses that are possible using the BrainMap database and coordinate-based ALE meta-analyses, along with some examples of how these tools can be applied to create a probabilistic atlas and ontological system of describing function–structure correspondences.

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