Genetics of Epilepsy and Refractory Epilepsy

Genetics of Epilepsy and Refractory Epilepsy

Alberto Lazarowski, Liliana Czornyj
ISBN: 9781615045327 | PDF ISBN: 9781615045334
Copyright © 2013 | 119 Pages | Publication Date: 03/01/2013

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Epilepsy affects approximately 3% of the population, and is usually defined as a tendency to experience recurrent seizures arising from periodic neuronal hyperexcitability of unknown causes. Different genetic factors, through various mechanisms, can cause this abnormal neuronal behavior. The etiology of epilepsy is a major determinant of clinical course and prognosis. Many of the genes that have been implicated in idiopathic epilepsies code for ion channels, whereas a wide spectrum of syndromes where epilepsy is a main clinical feature are caused by mutated genes that are involved in functions as diverse as cortical development, brain malformations, mitochondrial function, and cell metabolism. Similarly, different conditions as hypoxia, trauma, infections, or metabolic unbalances can develop epileptic syndromes where upregulation of several genes could be related to the epileptogenic mechanisms. The most common human genetic epilepsies display a complex pattern of inheritance, and the susceptible genes are largely unknown. However, major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. As we continue to unravel the molecular genetic basis for epilepsies, it will increasingly influence their classification and diagnosis. A majority of epileptic patients may control their crisis with anticonvulsant drugs, however 30-40% became refractory to pharmacological therapies and require surgical treatment. The challenge of the molecular revolution will be the design of the best treatment protocols based on genetic profiles that include both the specific mechanistic etiology of the epilepsies, as well as their potential refractory behavior to current medications. This includes also the design of new therapeutic agents and targets, so as to reduce the number of cases with refractory epilepsy and epileptogenesis, and perhaps avoid the current surgical treatment (a procedure that was first described more than 4000 years ago) except as a last option.

Table of Contents

What Is Epilepsy?
Resting Potential
Action Potential
Are There Any Genetic Bases for Epilepsy?
Ligand-gated Ion Channels
Acetylcholine Receptors CHRNA4, CHRNB2, and CHRNA2
Ion Channels
Sodium Channels
Potassium Channel Subunit Mutations with LOF Effects
Voltage-gated Calcium Channel Mutations and Genetic Susceptibility
GABA Receptor Subunit Mutations (Chloride Channel)
Copy Number Variants and Comorbidities
Susceptibility Genes for Complex Epilepsy
Glycine Receptors
Ionotropic Glutamate Receptors
G-protein-coupled Receptors
Metabotropic Glutamate Receptors
Other Genetic Causes of Epilepsy
Mitochondrial Inheritance and Myoclonic Epilepsy with Ragged Red Fibers
Leucine-rich Glioma Inactivated Gene 1 (LGI1)
Inborn Errors of Metabolism and Epilepsy
Epilepsy and NMDs
FOLR1 Gene Mutation
Lysosomal Storage Disorders
The Solute-carrier Gene Superfamily and Epilepsy
Genes Related with Different Epileptic Syndromes
Genetic Mechanisms of Drug Resistance in Epilepsy
Definition of Drug Resistance in Epilepsy
Genetics of Drug Response in Epilepsy
Drug Transport System
ABC Transporters
ABC Transporters and RE
MDR1 (ABCB1) Gene Variants
The BBB's Role in Pharmacoresistance in Epilepsy
Induction of ABC Transporters: Is the Acquired Refractoriness an Inducible Process?
Genes and Pharmacodynamic Modifications
Inducing the Expression of P-gp in Neurons: Is it to Induce Epileptogenesis?
Author Biographies

About the Author(s)

Alberto Lazarowski, Universidad de Buenos Aires, Instituto de Fisiopatolog
Alberto Lazarowski, PhD, is a biochemist trained at the School of Pharmacy and Biochemistry (FFyB) at the University of Buenos Aires, Argentina. He earned a masters in molecular biology and genetic engineering and a doctorate studying the role of folic acid in epileptic seizures in children. Currently, he is a professor of clinical biochemistry in the Department of Pharmacy and Biochemistry at the University of Buenos Aires. He was a postdoctoral fellow of the UICC (International Union Against Cancer), studying the MDR gene at UNC-Chapel Hill, and later he described for the first time the role of the MDR-1 gene in Argentine children with refractory epilepsy. Later, he developed the confirmatory experimental studies in rats at the IBCN (Instituto de Biología Celular y Neurociencias, "Prof. E. de Robertis," School of Medicine, University of Buenos Aires). Together, Dr. Czornyj and Dr. Lazarowski have studied several cases of pharmacoresistant epilepsies in children with overexpression of different ABC transporters in the brain epileptogenic areas associated with pharmacokinetic modifications of some AEDs and described the potential role of multidrug resistant proteins in refractory epilepsy and antiepileptic drug interactions. Both are members of GENIAR, an Ibero-Latin-American network of researchers in neuroscience (CYTED #610RT0405).

Liliana Czornyj, Hospital Nacional de Pediatria of Buenos Aires
Liliana Czornyj, MD, completed her postgraduate training in clinical pediatrics and child neurology. She is a past president of SANI (Child Neurology Society of Argentina) and a member of the International Child Neurology Association (ICNA) and LACE (Epilepsy League of Argentina). For 25 years, she has worked at the Neurology Department of the Prof. Dr. Juan P. Garrahan Hospital Nacional de Pediatría of Buenos Aires, Argentina. She is coauthor of several textbooks of clinical child neurology, neuroinfectology, and neuropharmacology.

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