Recent Advances in the Genetics of Epilepsy: Insights from Human and Animal Studies

Abstract

Summary: Progress in understanding the genetics of epilepsy is proceeding at a dizzying pace. Due in large part to rapid progress in molecular genetics, gene defects underlying many of the inherited epilepsies have been mapped, and several more are likely to be added each year. In this review, we summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, and correlate these advances with rapidly expanding information about the mechanisms of epilepsy gained from both spontaneous and transgenic animal models. We also provide practical suggestions for clinicians confronted with families in which multiple members are afflicted with epilepsy. Key Words: Epilepsy-GeneticsHuman-Pathophysiology-Animal models.Over the past few years, there has been an explosion of information about the genetic basis of epilepsy and epilepsy syndromes. Some of these advances have been documented in recent reviews (1-6). In parallei with advances in understanding the genetics of human epilepsies, several spontaneous and transgenic animal models of inherited epilepsy have been produced. These approaches will expand our ability to dissect cellular mechanisms of seizure generation and propagation and help us to move from serendipity to rationality in designing targeted therapies for seizure disorders (7,8). In this review we summarize the recent progress in mapping genes for human epilepsy, describe some relevant animal models of genetic epilepsy, and examine the relation between gene defects and the cellular mechanisms of epilepsy. Finally, we provide practical suggestions for clinicians caring for patients and families with inherited epilepsies. Clinical details of the various epilepsy syndromes, available elsewhere, are largely omitted here.Epilepsy, characterized by recurrent seizures, results from excessive synchronous firing of neurons in cortical networks. A number of intricately linked mechanisms at the network, cellular, subcellular, and molecular levels

Overview of the Current Animal Models for Human Seizure and Epileptic Disorders

“…As shown in Tables 1 and 3, only a few characterized animal models are available for the number of Mice (e.g., weaver, other mutant strains) (17,18,56,144) severe neonatal, early and late childhood, and adolescence seizure disorders. One of the most common seizure disorders observed in children is febrile seizures.…”

MRS Studies of the Role of Altered Glutamate and GABA Neurotransmitter Metabolism in the Pathophysiology of Epilepsy

“…GABA is the major inhibitory neurotransmitter in the mammalian brain, including humans. Reviews by several investigators have stressed the role of GABA in epilepsy and emphasized the developmental aspects of GABA physiology, with implications for childhood epilepsy (van den Pol et al, 1998;Powell et al, 2003;Berkovic and Scheffer, 1999;Prasad et al, 1999). Animal models using advanced molecular genetic techniques such as knockout mutations have identified the role of genes affecting ion channels, the synapse (including release and uptake of neurotransmitters) synaptic receptors and the neural network that result in epilepsy.…”

The Wakayama Epileptic Rat(WER), a New Mutant Exhibiting Tonic-clonic Seizures and Absence-like Seizures.

“…In the last decade, many studies with animal models of inherited epilepsy have contributed to our understanding of epilepsy mechanisms [4][5][6]17]. Inherited epilepsies have been found to be attributable to a single gene defect modulating functions of the ionic-channel, the voltage-gated channel, the neurotransmission and the neural network (reviewed in [17]). However, common epilepsies are transmitted in a complex, polygenic or pleiotropic, manner [3,17].…”

“…Inherited epilepsies have been found to be attributable to a single gene defect modulating functions of the ionic-channel, the voltage-gated channel, the neurotransmission and the neural network (reviewed in [17]). However, common epilepsies are transmitted in a complex, polygenic or pleiotropic, manner [3,17]. With rapidly advancing rodent genomic technologies and resources, studies of the polygenic epilepsies are in progress [9,10,14].…”