Genetic epilepsy syndromes without structural brain abnormalities: clinical features and experimental models

Abstract

Research in genetics of epilepsy represents an area of great interest both for clinical purposes and for understanding the basic mechanisms of epilepsy. Most mutations in epilepsies without structural brain abnormalities have been identified in ion channel genes, but an increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing. Targeted molecular diagnosis is now available for different forms of epilepsy. The identification of epileptogenic mutations in patients before epilepsy onset and the possibility of developing therapeutic strategies tested in experimental models may facilitate experimental approaches that prevent epilepsy or decrease its severity. Functional analysis is essential for better understanding pathogenic mechanisms and gene interactions. In vitro experimental systems are either cells that usually do not express the protein of interest or neurons in primary cultures. In vivo/ex vivo systems are organisms or preparations obtained from them (e.g., brain slices), which should better model the complexity of brain circuits and actual pathophysiological conditions. Neurons differentiated from induced pluripotent stem cells generated from the skin fibroblasts of patients have recently allowed the study of mutations in human neurons having the genetic background of a given patient. However, there is remarkable complexity underlying epileptogenesis in the clinical dimension, as reflected by the fact that experimental models have not provided yet results having clinical translation and that, with a few exceptions concerning rare conditions, no new curative treatment has emerged from any genetic finding in epilepsy.

Fig. 1

Experimental models used for functional analyses of epileptogenic mutations/variants, in particular for ion channel genes. cRNA cloned RNA containing the sequence of the gene of interest and the mutation/variant under study; cDNA cloned DNA containing the sequence of the gene of interest and the mutation/variant under study; iPS induced pluripotent stem cells

Fig. 2

Basic structure of main voltage- and ligand-gated ion channel proteins involved in genetic epilepsy. The structure of the subunits targeted by mutations/variants identified in genetic forms of epilepsy are shown. The names of the genes and the forms of epilepsy in which they are involved are indicated below the diagram of the protein. Nav voltage-gated sodium channels; Cav3.2 voltage-gated calcium channels, T-type-1H; Kv7 voltage-gated potassium channels, M-type; KCa4.1 sodium-activated potassium (KNa) channel, SLACK-SLO2.2 type; GABA-A gamma-aminobutyric acid receptor, type A; Ach nicotinic acetylcholine receptor; NMDA glutamate receptor, N-methyl-D-aspartate (NMDA) type; DS Dravet syndrome; GEFS+ generalized (genetic) epilepsy with febrile seizures plus; EE epileptic encephalopathies; BNIFS benign neonatal-infantile familial seizures; BNIS benign neonatal familial seizures; IGE idiopathic generalized epilepsies; MMPSI malignant migrating partial seizures of infancy; ADNFLE Autosomal dominant nocturnal frontal lobe epilepsy; EAS epilepsy–aphasia syndromes

Fig. 3

(a) General structure of a single subunit of the nicotinic receptor. (b) Nicotinic receptors are formed by 5 subunits (pentamers), symmetrically arranged to delimit a pore through which cations flow, with Na⁺ and Ca²⁺ incoming, and K⁺ outgoing. Nine different types of α-subunits and 4 different types of β-subunits are known. Isoforms for subunits δ, ε, and ϒ are not yet known. Numerous receptor subtypes that have specific anatomic locations (e.g., muscle or neuronal) are generated by multiple combinations of different types of these subunits. In the central nervous system, the pentameric structures of the receptor are composed of α-subunit homodimers or of α-subunits/β-subunits combinations. (c) Top view of the structure of a neuronal nicotinic receptor composed by 2 α4-subunits (CHRNA4) and 3β2-subunits (CHRNB2). Abnormalities in this receptor, caused by mutations of its subunits, cause nocturnal frontal lobe epilepsy