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Epilepsy
Genetic Determinants of Seizures and Epilepsy
Russell J Buono, PhD,
1
Dennis J Dlugos, MD, MSCE
2
and Thomas N Ferraro, PhD
3
1. Chief, Research and Development, Research Service, Veterans Affairs Medical Center, Coatesville; 2. Associate Professor, Department of Pediatrics,
The Children’s Hospital of Philadelphia; 3. Research Associate Professor, Departments of Psychiatry and Pharmacology, University of Pennsylvania
Abstract
Epilepsy is a group of common neurological disorders characterized by heterogeneous clinical presentation. The etiology of epilepsy is
multifactorial, involving the influence of multiple gene variants interacting with factors in the environment. Certain rare forms of epilepsy have
been attributed to mutations in a single gene, and although the list of such genes that are sufficient to produce epilepsy when mutated is
growing steadily, they are directly relevant to only a very small fraction of all cases of epilepsy. Genetic influences in common forms of epilepsy
have been more difficult to identify and future studies will focus on strategies to hasten the discovery process. The combination of translational
research involving animal models and advances in genome technology will facilitate the identification of genetic variations that influence
seizure susceptibility and contribute to the risk for developing common epilepsy. Application of genetic strategies to clinically well-characterized
epilepsy patients will provide the added benefit of yielding data that are also relevant to the discovery of genes that influence responsiveness
to the effects of antiepileptic drugs. Thus, future research on the genetic influences in epilepsy is anticipated to provide insight into both the
underlying biological basis of seizures and potential targets that may be used to develop new treatments.
Keywords
Epilepsy, seizures, genetics, pharmacogenetics, genetic susceptibility, genetic association, animal models
Disclosure and Acknowledgements: The authors’ research is supported by National Institutes of Health (NIH) grant NS040554. They have no conflicts of interest to declare.
Received: November 17, 2008 Accepted: July 27, 2009
Correspondence: Thomas N Ferraro, PhD, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 S 31st Street, Philadelphia, PA 19104.
E:
Tnf@mail.med.upenn.edu
Epilepsy is a term used to describe over 40 different human seizure are classified as symptomatic since there is a readily understandable
disorders that vary in clinical and electroencephalographic (EEG) cause for the seizures. However, in most cases the cause of epilepsy
characteristics. It is one of the most common neurological disorders is unknown. Epilepsies of unknown cause are divided into two
and occurs in about 1% of the population, independent of geography, categories: the first is cryptogenic epilepsy, meaning that the cause is
ethnicity, or gender.
1
Seizures occur when the brain is disrupted by suspected to be induced by a pathology that is below the limit of
abnormal neuronal activity. Having two or more unprovoked seizures detection of the available diagnostic screens; the second is idiopathic
is a working definition of epilepsy that is used commonly by epilepsy, meaning the cause is most likely related to a genetic
physicians. The focus of ‘epileptic activity’ can be centered in any predisposition. These definitions are used with regularity among
region of the brain, although cerebral cortex, thalamus, and limbic neurologists who specialize in treating patients with epilepsy.
structures are most often involved. In some types of epilepsy, the
abnormal activity is confined to a specific brain region, and these are Molecules
classified as focal, partial, or localization-related epilepsy. In other A significant amount of research on epilepsy is dedicated to
epilepsy subtypes, the abnormal neuronal activity does not have a understanding the pathophysiology of seizures from a molecular
clear focus, or may be thalamic or subcortical in nature, and these are perspective. This research seeks to gain a comprehensive knowledge
classified as generalized epilepsy. Clinical classification of epilepsy of how DNA, RNA, and proteins interact to affect the cellular
subtypes and syndromes is complex and somewhat controversial; components of the central nervous system (CNS) that regulate neural
however, all agree with a major division between focal and excitation and inhibition. The molecules and their interactions
generalized epilepsy. combine to create cells with specific properties that allow them to
form circuit networks and the higher-order electrical characteristics of
Causes of Epilepsy the brain. Initially, molecular research focused on the main excitatory
Seizures can be caused by brain tumors, vascular malformation, CNS neurotransmitter, glutamate, and the main inhibitory CNS
encephalitis, or as a result of traumatic brain injury. These epilepsies neurotransmitter, gamma aminobutyric acid (GABA). Thus, glutamate
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