Epileptogenesis and functional lability of the genome

Abstract

Genetically determined effects on the development of epilepsy are diverse. First of all, they are aimed at changing the activity of ion channels and functional proteins (including synaptic proteins). Epigenetic regulation of genome activity is also considered one of the most important factors in the development of both single paroxysms and epilepsy as a disease. To date, numerous associations between gene disorders and epilepsy have been described. They are detected in genes of very different determinant activity, and identical clinical phenotypes, such as West, Dravet, Ohtahara, and Lennox—Gastaut syndromes, can be observed when different genes are affected. Within a single gene-associated condition, multiple mutations of different types can occur, and distinct clinical features of the disease correspond to distinct types of mutations. Moreover, involvement of a single gene can induce several mechanisms of epileptogenesis (impaired receptor regulation, permeability of the blood-brain barrier, impaired neuronal differentiation, etc.). Epigenetic mechanisms provide genome functional lability by changing the accessibility of individual DNA parts without altering their structure. The genome-altering mechanisms during epileptogenesis include the methylation of genes encoding voltage-gated calcium and potassium channels, as well as genes that affect neuronal plasticity, signaling pathway function, and neuroinflammation processes. Histone acetylation can be considered both as a maintenance and progression factor of the epileptic process and as a «rapid response agent» in status epilepticus. Non-coding RNAs regulate neuroinflammation, apoptosis, synaptogenesis, synaptic plasticity, abnormal sprouting, and neural network remodeling. The circle is closed by pathogenic variants of genes that determine the synthesis of epigenetic effectors. Expanding knowledge about the genome lability mechanisms is one of the prerequisites for success in finding new ways to treat epilepsy.

Affiliated Institutions

• Ministry of Health HR
• Russian Medical Academy of Continuous Professional Education RU

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