This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neuronal excitability, and thus epileptogenicity, is critically governed by the interaction of voltage- and ligand-gated ion channels and mutations of ion channel genes are now recognized as an important cause of independently defined inherited epilepsy syndromes and cardiac arrhythmias. Recent evidence indicates that a subset of these genes is co-expressed in heart and brain. There is extensive clinical and experimental evidence supporting coexistence of seizures and cardiac arrhythmias, and many clinical reports suggest that """"""""arrhythmogenic epilepsy"""""""" is the pathophysiological mechanism of sudden unexplained death in epilepsy (SUDEP). Long QT syndrome (LQTS) has been increasingly recognized as a cause for idiopathic cardiac arrhythmia and sudden cardiac death. Seven LQT genes (SCN5A, KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, and ANKB) have been identified. Mutations alter electrophysiological properties of a channel thus predisposing the heart towards fatal arrhythmias. Research data originating from our laboratory demonstrated that SCN5A is selectively co-expressed in heart and the brain limbic region, a network inherently prone towards epileptogenesis. KCNH2, KCNE2, ANKB, and KCNJ2 genes are also expressed in brain. Moreover, we found an increased incidence of seizure history in the cohort of patients with an idiopathic LQTS. The clinical phenotype of channelopathies can vary widely according to the position of the mutation within the channel as well as according to the total mutational load. Specific point mutations and/or their combinations within and between LQT genes can lead to unexpected effects. Some might favor a cardiac presentation (such as LQTS), some an epileptic phenotype, some may trigger both overt clinical seizures and fatal cardiac arrhythmias and ultimately lead to SUDEP. I therefore propose an increased prevalence of epilepsy and epileptiform abnormalities in patients with idiopathic long QT syndrome (LQTS) and the existence of two distinct clinical phenotypes (LQTS + epilepsy vs. sole LQTS) with corresponding specific LQT genotypes. This project will extend our preliminary data and test involvement of LQT genes in epilepsy by (1) determining the prevalence of epilepsy and epileptiform traits in the LQTS cohort, (2) defining the frequency and the spectrum of coding single nucleotide polymorphisms (cSNPs) in LQT genes of the LQTS patients, and by (2) correlating the two LQTS phenotypes with and without epilepsy with a corresponding genotypes. This research may help to determine the roles that LQT genes may play in the etiology of seizures and SUDEP. It may also assist in defining an epilepsy population at risk for sudden death, which would allow initiation of life-saving preventative measures and the design of gene-specific therapy for the affected patients. HYPOTHESIS There is an increased prevalence of epilepsy and epileptiform abnormalities in patients with idiopathic long QT syndrome (LQTS) and two distinct clinical phenotypes (LQTS + epilepsy vs. sole LQTS) have corresponding specific LQT genotypes.
SPECIFIC AIMS Aim 1a: Define the prevalence and the spectrum of seizures and epileptiform abnormalities in patients with idiopathic long QT syndrome (LQTS).
Aim 1 b: Define the frequency and the spectrum of coding single nucleotide polymorphisms (cSNPs) in LQT genes of patients with idiopathic LQTS and compare the genotypes of cases with LQTS + epilepsy vs. genotypes of cases with a sole LQTS phenotype in a case control study. BACKGROUND AND SIGNIFICANCE Epilepsy and Channelopathies. Epilepsy is one of the most common neurological disorders, and up to 3% of population can be expected to have epilepsy at some time in their life (1). Almost 69% of all epilepsies are idiopathic, and while in most cases their true etiology is unknown, a genetic contribution has now been estimated to be present in up to 40% of patients with epilepsy (2). Over 60 genes for various subtypes of epilepsy have been reported in the last several years (3). One important functional subgroup is composed of voltage- and ligand-gated ion channels (4), and these CNS channelopathies are now recognized as an important cause of defined, inherited epilepsy syndromes. Coexistence of Epilepsy with Cardiac Arrhythmias. Epileptic seizures commonly result in changes of cardiac rate (5-8). Sinus tachycardia is by far the most common accompaniment of partial seizures and is seen in 54-96% of cases (5,7,8). Ictal bradyarrythmias are less frequent, (9) present in 3.3-17% of partial seizures. (6,10). While tachycardia would normally accompany muscular exertion, the basis of ictal bradyarrythmias is not known. Some of the typical features that have been found in cases of ictal bradycardia are following: males are much more commonly affected, and over 80% of the cases reported in the literature had temporal lobe epileptic discharges precipitating the bradyarrhythmia (11). The primary cerebrogenic nature of bradyarrhythmias and co-existence of cardiac arrhythmias and seizures has been convincingly demonstrated by several authors and classified as """"""""arrhythmogenic epilepsy"""""""". (5,6,10-14). It has become evident that ictal bradycardia and asystole may be life threatening and contribute to the syndrome of sudden unexplained death in epilepsy. (15). Most recently, Tigaran et al. described a case with repeated episodes of seizures related to complete atrio-ventricular block (14). Sudden Unexplained Death in Epilepsy (SUDEP). Sudden unexplained death in epilepsy (SUDEP) defines sudden unexpected mortality that occur in benign circumstances in otherwise well individuals with epilepsy with or without evidence of seizure and excluding documented status epilepticus. Postmortem examination does not reveal the cause of death(16). There is compelling evidence that the epilepsy population faces death at a rate two to three times higher than the general population (17), and it ranks as a primary cause of death in epilepsy. Seizure severity appears to be consistently the strongest risk factor. Other commonly cited factors predisposing for SUDEP are: male sex, age 20-40 years, generalized seizures, early onset epilepsy, multiple anticonvulsant medications and poor compliance with medications (18-20).The mechanism of SUDEP is not fully understood. A number of studies dealing with this subject came to the conclusion that the fatal event is most commonly temporally related to seizures, is generally unwitnessed, and frequently occurs in sleep (22-23). A primary respiratory cause has been considered. Secondary cardiac dysrhythmia of cerebral origin or """"""""arrhythmogenic epilepsy"""""""" is yet another mechanism implicated in SUDEP. Long QT Syndrome (LQTS). LQTS has been increasingly recognized to underlie syncopal episodes and fatal ventricular arrhythmias in young people. It is estimated that as much as one third of sudden unexplained death is due to occult LQTS (54). While the exact incidence in the general population is not known, recent speculations suggest LQTS to be as common as cystic fibrosis (1/3000) (24). It is manifested either as an inherited, sporadic, or acquired disorder. The ECG hallmark is a prolongation of a rate adjusted QT interval (QTc). Interestingly, there is a subgroup of patients that are predisposed to fatal cardiac dysrhythmias during sleep, a feature that has also been observed in SUDEP (25). Verified epileptic seizures in LQT patients have been identified in epilepsy monitoring units, although these cases were not confirmed to be channelopathies by genotype analysis. It is also likely that patients presenting to epilepsy monitoring units with convulsive syncope (26) suffer from a subclinical LQT syndrome. Furthermore, true tonic/clonic and partial seizures may often co-exist with syncopal episodes (27-31). A prolonged QT interval is present only about 40% of the time in a routine ECG recording (32). It is likely that the occult ECG character of the LQTS is the reason that a clinical correlation between dysrhythmias of heart and brain has not previously been suspected or confirmed. To date, seven LQTS genes containing more than 200 mutations have been identified. The IKS and IKr potassium channel mutations as well as the majority of SCN5A gene (INa) mutations identified so far prolong the plateau phase of the cardiac action potential. The Kir2.1 channel contributes no repolarizing current during the plateau phase of the cardiac action potential but a substantial one in the repolarization phase. Defects in all of these channels can delay myocardial membrane repolarization, manifested as a lengthening of QT interval on ECG. Some SCN5A mutations cause premature closure of the sodium channel. Either situation alters the cardiac action potential and creates a substrate for reentrant arrhythmia. Other, non-channel genes (ryanodine receptor gene RYR2 and calsequestrin 2 gene CASQ2) have also been linked to cardiac arrhythmia, and are expressed in brain. The majority of sudden deaths/malignant arrhythmias occur under the circumstances of sudden sympathetic overactivity. The proposed pathogenic mechanism resulting from these mutations is that mutant channel inactivation kinetics are slowed by adrenergic input, thus prolonging channel open time, increasing cell depolarization, and favoring repetitive firing and seizures in the brain and tachyarrhythmias in the heart. A primary limbic seizure, with known effects on the autonomic nervous system, could also trigger a syncopal episode or even fatal arrhythmia (33,34);conversely, hemodynamic insufficiency from a primary arrhythmia might trigger abnormal depolarization and a secondary seizure in brain regions expressing the mutant channel. Since the clinical phenotype of channelopathies can vary widely according to the position of the mutation within the channel, some mutations might favor a cardiac presentation, others an epileptic one.
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