GABA-a receptor & Epilepsy

Association of specific GABA receptor mutations & distinct forms of epilepsy Introduction: • Discuss current literature on GABA receptor mutations and epilepsy • Aim of review: To understand potential associations between specific GABA receptor mutations and form of epilepsy associated with that particular mutation. • Describe epilepsy o Symptoms and causes o Classifications: generalized vs. localized (focal) o Genetic vs. acquired o Process of epileptogenesis • Discuss GABA receptors o Structure and function o Different subtypes o Distribution in brain o Synaptic vs. extra-synaptic Discussion: • Discuss various genetic GABA receptor mutations and associated forms of epilepsy o Mutations of alpha-1 subunit  Molecular mechanisms  A322D mutation- missense mutation on TM3 • Juvenile Myoclonic Epilepsy  975delC- single bp deletion- truncated TM3 • Child Absence Epilepsy o Mutations of beta-3 subunit  Molecular mechanisms  P11S, S15F- missense mutations • Child Absence Epilepsy  Haplotype 2- promoter in exon 1A • Child Absence Epilepsy o Mutations of gamma-2 subunit  Molecular mechanisms  R82Q mutation- missense mutation • Child Absence Epilepsy & Febrile Seizures  K328M –missense mutation between TM2 and TM3 • Febrile Seizures & Generalized Epilepsy with Febrile Seizures plus  Q40X- nonsense mutation N terminus • Dravet syndrome  R136X- nonsense mutation N terminus • Generalized Epilepsy with Febrile Seizures plus  W429X- nonsense mutation between TM3 and TM4 • Generalized Epilepsy with Febrile Seizures plus • Discuss phenotypic severity of different forms of epilepsy o Benign phenotypes: Generalized Epilepsy with Febrile Seizures plus & Juvenile Myoclonic Epilepsy o Severe phenotypes: Dravet Syndrome & Epileptic Encephalopathy • Discuss other potential factors that can impact GABA receptor function and lead to epileptic symptons o Metabolism & Homeostasis (temperature) o Epigenetics Conclusion: • Discuss the potential association between specific GABA receptor mutations and associated forms of epilepsy • Elucidate potential gaps in current understanding on GABA receptor mutations and epilepsy o Offer potential research & therapeutic targets