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Objective: To examine the role of mutations in GABRB3 encoding the b 3 subunit of the GABA A receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. Methods:We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. Results:We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant b 3 , together with a 5 and g 2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. Conclusions:Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism. Neurology ® 2017;88:483-492 GLOSSARY DS 5 Dravet syndrome; EE 5 epileptic encephalopathies; EOAE 5 early-onset absence epilepsy; ExAC 5 Exome Aggregation Consortium; FS 5 febrile seizures; GFS1 5 genetic epilepsies with febrile seizures plus; GGE 5 genetic generalized epilepsies; ID 5 intellectual disability; LGS 5 Lennox-Gastaut syndrome; MAE 5 epilepsy with myoclonic atonic seizures; WS 5 West syndrome; WT 5 wild-type.

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Since epilepsy is a chronic disease of the nervous system that requires long-term therapy and regular intake of antiepileptic drugs, good tolerability of therapy is crucial for the quality of life of these patients. The main aim of antiepileptic treatment is the creation of a balance between the efficacy and tolerability of therapy. This literature review analyzes tolerability and safety of antiepileptic therapy. We paid particular attention to valproate, a drug that has been used for the treatment of epilepsy for more than 57 years. Valproate remains a basic drug with high efficacy and well-studied safety and tolerability. This review also covers the problems of epilepsy aggravation in response to some antiepileptic drugs, effects of antiepileptic drugs on cognitive functions, behavior, and mental sphere, as well as the issues of tolerability and safety of antiepileptic drugs in women of reproductive age.

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