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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long QT syndrome (LQT) is an inherited cardiac disorder that causes syncope, seizures and sudden death from ventricular tachyarrhythmias. We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families. These mutations include two identical intragenic deletions and two missense mutations. These data suggest that SCN5A mutations cause LQT. The location and character of these mutations suggest that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.
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PMID:Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. 854 46

Recently, there has been intense excitement in the field of cardiac arrhythmias. Molecular genetic studies have led to significant progress in characterizing molecular mechanisms underlying long QT syndrome, an inherited cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias. Three long QT syndrome genes have been identified: SCN5A on 3p21-24, HERG on 7q35-36, and KVLQT1 on 11p15.5; all encode cardiac mycote ion channels. Molecular and electrophysiological characterization of these three long QT syndrome genes has led to identification of three critical electrical currents in the human heart (INa, IKr, IKa) and provides insight into our fundamental understanding of cardiac function. Genetic testing and gene-specific therapies are now available for some families with long QT syndrome.
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PMID:Molecular genetics of long QT syndrome from genes to patients. 924 89

Expression of the rat (RH-I/SkM2) and human (hH1/SCN5A) tetrodotoxin-resistant (TTX-R), voltage-sensitive sodium channels is thought to be specific to cardiac tissue. We detected RH-I/SkM2 mRNA in newborn rat brain using both RNase protection assay analysis and in situ hybridization and in adult rat brain using RNase protection assay analysis. This expression was observed primarily in developing limbic structures of the cerebrum and diencephalon, and in the medulla of the brain stem. Using RT-PCR analysis, we detected hH1/SCN5A mRNA in both fetal and adult human brain. Interestingly, mutations in the human cardiac sodium channel are known to lead to cardiac abnormalities, which result in arrhythmias and frequently in sudden cardiac death. If these mutant channels were also expressed in limbic regions of the brain, alterations in channel function could have drastic effects on the brain's signaling ability, possibly promoting seizure activity.
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PMID:The cardiac sodium channel mRNA is expressed in the developing and adult rat and human brain. 1113 23

Heterozygous mutations in genes encoding cardiac ionic channel subunits KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 are causally involved in the dominant form of long-QT syndrome (LQTS) while homozygous mutations in KCNQ1 and KCNE1 cause LQTS with or without congenital deafness. In addition, two homozygous HERG mutations have been associated with severe LQTS with functional atrioventricular conduction anomalies in young children. A 2:1 atrioventricular block (AVB) with a major QTc prolongation (526 ms) was evidenced in a 5-year-old boy referred for syncope and seizure. LQTS was diagnosed and beta-blocking therapy initiated leading to normal atrioventricular conduction. Electrophysiological study provided support that location of the AVB was infra-Hisian. DNA analysis was performed in the proband and in asymptomatic family members. A novel missense mutation, V1777M, in the early C-terminal domain of SCN5A was identified. The proband was homozygous while the parents and two siblings were heterozygous carriers. Homozygote and heterozygote expression of the mutant channels in tsA201 mammalian cells resulted in a persistent inward sodium current of 3.96+/-0.83% and 1.49+/-0.47% at -30 mV, respectively, which was dramatically reduced in the presence of tetrodotoxin. This study provides the first evidence for a homozygous missense mutation in SCN5A and suggests that LQTS with functional 2:1 AVB in young children, a severe phenotype associated with bad prognosis, may be caused by homozygous or heterozygous compound mutations not only in HERG but also in SCN5A. The full text of this article is available at http://www.circresaha.org.
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PMID:Homozygous SCN5A mutation in long-QT syndrome with functional two-to-one atrioventricular block. 1146 28

Na+ channelopathies that prolong membrane depolarization lead to neuronal bursting, abnormal network synchronization, and various patterns of episodic neurological disorders, including epilepsy. Two distinct pathways exist for generating epileptic phenotypes based on inherited disorders of voltage-gated Na+ ion channels. The first pathway is direct, involving mutations in genes encoding the pore-forming alpha1 and regulatory beta subunits of the channel that directly alter current amplitude or kinetics. These mutations favour repetitive firing and network hyperexcitability, although often the circuits most vulnerable to functional alterations are not easy to identify and the emergent clinical phenotypes are difficult to predict. The second pathway involves mutation of other genes that lead to downstream modifications in Na+ channel expression. Two clinically relevant examples of localization-related vulnerability in brain are described that illustrate how specific phenotypes arise from both direct and secondary pathways. Selective expression of the cardiac SCN5A channel within limbic regions of brain may explain why mutation of the gene for this tetrodotoxin-insensitive current may be associated with seizures. Ectopic expression of type II Na+ channels along axonal internodes in hypomyelinated brain may reveal why deletion of the myelin basic protein gene leads to subcortical seizure patterns. Analysis of these models offers insight into developmental processes that control the cellular expression and plasticity of Na+ channel genes, and will help to clarify mechanisms of hereditary Na+ channel-based epileptogenesis.
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PMID:Sodium channel gene expression and epilepsy. 1177 41

Long QT Syndrome (LQTS) is a cardiac disease characterized by a prolonged QT interval on a surface electrocardiogram (ECG) and by clinical symptoms such as seizures, syncope, and cardiac sudden death. At present, causal mutations of LQTS have been identified in five cardiac ion-channel genes. Because a causal mutation is usually unique to a specific family and can be located in any region of any of these five genes, a mutation analysis effort may require screening of the complete coding regions of each of these genes. The causative nature of a detected mutation can then be determined either by family history or by functional studies, such as the electrophysiological signature of the mutation. Here we describe a mutation analysis of an LQTS patient who carries two heterozygous missense mutations in two different LQTS genes. The first mutation identified, A572D in SCN5A, was not linked with clinical LQTS features in the two other mutation carriers in the family; neither was it identified in 90 healthy controls. Therefore, this mutation most likely has either a mild effect on cardiac ion-channel function or represents a very rare polymorphism. The second mutation, V254M in KCNQ1, co-segregated with higher QT intervals and symptoms in other family members, and was previously reported in another LQTS family. Because the clinical LQTS symptoms are most pronounced in the proband, a combined effect of both mutations cannot be excluded, although no functional data are available to support such an hypothesis. We conclude that, for newly presented LQTS cases, a mutation analysis strategy should routinely screen the complete coding region of all LQTS genes, followed by an evaluation of the identified mutation(s) in conjunction with family or functional data.
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PMID:Mutation analysis in congenital Long QT Syndrome--a case with missense mutations in KCNQ1 and SCN5A. 1282 Jul 4

Since 1992, the Brugada syndrome has been increasingly recognized worldwide, although its incidence and distribution remain unclear. In Asia, several cases have been reported in Japan, Thailand, Singapore, and Vietnam. However, little information is available from the Chinese population. Since June 1997, we have identified 10 patients with the diagnosis of the Brugada syndrome from six hospitals in Taiwan. All patients were male with the mean age of 46 +/- 7 years (range 36-61). They all had a normal chemistry profile, coronary angiography and echocardiography. Clinical presentations varied from seizure and syncope to sudden cardiac death. MRI and ultrafast CT of the heart did not show any abnormalities. Sustained ventricular tachycardia/ventricular fibrillation (VF) was induced in 7 of 8 patients who underwent an electrophysiologic study. The pharmacological provocation test was positive in 4 of 5 patients. One of the 4 patients who had a genetic study showed SCN5A gene mutation. An implantable cardioverter defibrillator (ICD) was implanted in 8 patients. During a mean follow-up of 29 +/- 17 months (range 2-54), 3 of 8 patients who had an ICD received appropriate ICD discharges after implantation. These 3 patients who were subsequently treated with antiarrhythmic agents have had no further recurrent ICD discharges. Two patients who refused ICD implantation are alive and well without taking antiarrhythmic agents. Our study showed that the clinical characteristics of our patients are similar to those described in the literature and that ICD is an effective treatment modality for patients with recurrent VF. However, antiarrhythmic agents may be beneficial for suppressing arrhythmia recurrences in selected patients.
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PMID:Characteristics of Chinese patients with symptomatic Brugada syndrome in Taiwan. 1284 44

Multiple mutations in several ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and KCNJ2) have been shown to cause autosomal dominant long QT syndrome (LQTS), a familial cardiac disorder that causes syncope, seizures, and sudden death. Due to their multiple loci and considerable size, mutation detection in these genes represents a challenge that is only partially met by the conventional screening method of single-stranded conformational polymorphism (SSCP). The recently introduced denaturing high-performance liquid chromatography (dHPLC) offers a promising new method for a fast and sensitive analysis of PCR-amplified DNA fragments. To test the applicability of dHPLC in the molecular diagnosis of LQTS, we first assessed a cohort of 192 patients from our International LQTS Registry for 14 previously identified mutations (including 10 different missense mutations, 1-bp, 2-bp, 3-bp, and 9-bp deletion mutations), and 2 polymorphisms in the LQTS potassium and sodium channel genes. Applying empirically determined exon-specific melting profiles, all mutations (including four previously undetectable by SSCP) were readily identified by dHPLC. We conclude that the dHPLC technology is a highly sensitive and efficient method for the molecular analysis of LQTS, and the same PCR amplicons developed for SSCP testing can be directly used for dHPLC assay.
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PMID:Denaturing high-performance liquid chromatography quickly and reliably detects cardiac ion channel mutations in long QT syndrome. 1464 2

The objective was to analyze the clinical and molecular findings in a cohort of neonates and infants with the autosomal dominant long QT syndrome (LQTS). Those affected face a high risk of ventricular arrhythmia resulting in syncope, seizure or sudden death. Blood samples submitted for molecular diagnostic studies on 7 infants were subject to DNA extraction and mutation analysis of 18 selected exons in 5 LQTS genes (KCNQ1, HERG, SCN5A, KCNE1, and KCNE2). We detected 11 mutations in these 7 patients. Four patients had 2 mutations in 1 gene (compound heterozygotes) or 2 different genes (digenic inheritance), while 3 patients had 1 mutation each. Except for 1 mutation in KCNE1, all other mutations were detected alone or in combination within HERG and the SCN5A genes. Four of the mutations we found are novel. The lethal nature of the LQTS demands careful attention to the family history and prompt and precise diagnosis and treatment with serious consideration of endocardial pacemaker implantation. While much larger studies are needed, our data suggest that compound heterozygotes or those with 2 mutations in different genes are likely to have a more severe LQTS including early manifestations in neonates and infants.
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PMID:Gene sequencing in neonates and infants with the long QT syndrome. 1637 39

Fever can precipitate ventricular tachycardia in adults with Brugada syndrome, but such a link has not been reported in children. A 21-month-old white girl presented repeatedly with decreased conscious level and seizures during fever. During a typical episode, rapid ventricular tachycardia was documented. The resting 12-lead electrocardiogram revealed a Brugada electrocardiogram signature. Resting electrocardiograms of the asymptomatic brother and mother were normal, but fever in the mother and pharmacologic stress with ajmaline in the brother revealed Brugada electrocardiogram features. Genetic testing revealed an SCN5A mutation in the affected family members.
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PMID:Brugada syndrome masquerading as febrile seizures. 1742 Feb 62


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