Pathophysiological Mechanisms Fostering Developmental and Epileptic Encephalopathies (DEE): a Complex Interplay between Genetics, Inflammation and Neurodegeneration.

Abstract

Purpose of the review: Preclinical and clinical evidence support the notion that in Developmental and Epileptic Encephalopathies (DEEs) both neurodevelopmental and progressive alterations coexist. Several studies have contributed to the identification of pathophysiological mechanisms underlying DEEs, allowing novel interpretative meanings regarding the mechanisms involved in the progression of DEE symptomatology. The purpose of this review is to critically discuss emerging evidence linking DEEs, genetics, inflammation, and neurodegeneration.

Recent findings: In the last two decades, genetic findings have highlighted the role of cellular processes involved in both early neurodevelopment and neurodegeneration. In this scenario, evidence linking both autophagic and synaptic dysfunction to DEE provides the needed bridge between such pivotal processes for neuronal homeostasis and neurodegeneration. Furthermore, genetic defects affecting ion currents and cellular osmolarity, cytoskeletal structure and integrity of myelinated axons, neuronal morphology, and purine metabolism have been found to underlie DEE with progressive course. Recent evidence also demonstrates that neuroinflammation during gestation and in the immature brain can induce immune priming and increase the risk of developing DEEs. The phenotypic evolution of many DEEs beyond early childhood is still poorly understood and hardly preventable. Recent studies showed that DEEs, at least some of them, may be the consequence of early inflammatory and neurodegenerative dysfunctions with a variable severity determined by specific genetic and epigenetic factors. These findings open new avenues for uncovering the underpinnings of DEEs progression and symptomatology.