Developmental and epileptic encephalopathies (DEEs) are a group of neuropediatric diseases associated with epileptic seizures, severe delay or regression of psychomotor development, and cognitive and behavioral deficits. What sets DEEs apart is their complex interplay of epilepsy and developmental delay, often driven by genetic factors. These two aspects influence one another but can develop independently, creating diagnostic and therapeutic challenges. Intellectual disability is severe and complicates potential treatment. Pathogenic variants are found in 30–50% of patients with DEE. Many genes mutated in DEEs encode ion channels, causing current conduction disruptions known as channelopathies. Although channelopathies indeed make up a significant proportion of DEE cases, many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption of dendrite and axon growth, maintenance and synapse formation abnormalities —synaptopathies. Here, we review recent publications on non-channelopathies in DEE with an emphasis on the mechanisms linking epileptiform activity with intellectual disability. We focus on three major mechanisms of intellectual disability in DEE and describe several recently identified genes involved in the pathogenesis of DEE.

The high prevalence of diagnosed cases of severe neurological disorders, a significant proportion of which are epilepsy, contributes to a high level of mortality and disability in the population. Neurotrophic factors BDNF and GNDF are considered promising agents aimed at increasing the central nervous system’s adaptive potential for the development of the epileptiform activity. Despite the pronounced neuroprotective and anticonvulsant potential, an appropriate way to stimulate these endogenous signaling molecules with minimal risk of side effects remains an open question. Herein, we assessed the safety of gene therapy using original adeno-associated viral constructs carrying the genes of neurotrophic factors BDNF and GDNF in the early postnatal period of development of experimental animals. The intraventricular injection of AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs into newborn mice was found to provide persistent overexpression of target genes in the hippocampus and cerebral cortex in vivo for four weeks after injection. The application of viral constructs has a multidirectional effect on the weight and body length characteristics of mice in the early postnatal period; however, it ensures the animals’ resistance to the development of seizure activity under audiogenic stimulation in the late postnatal period and preserves basic behavioral reactions, emotional status, as well as the mnestic and cognitive abilities of mice after simulated stress. Our results demonstrated the safety of using the AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs in vivo, which indicates the expediency of further testing the constructs as therapeutic anticonvulsants.

One of the least studied but clinically severe forms of epilepsy is seizures with prenatal manifestations. Our understanding of epilepsy disorders has advanced substantially; numerous disease-associated genes have been identified, classifications have been refined, and underlying mechanisms and diagnostic approaches have been elucidated. However, one group of patients—those with seizures before the birth—has remained largely overlooked by researchers, despite numerous similar clinical cases reported over the past two decades. To date, only two genes, SCN2A and SCN8A, have been shown to have pathogenic variants that are reliably related to fetal epilepsy. Yet, how many genes are truly involved? This review will examine the known molecular foundations of epilepsy with prenatal onset. The prevalence of fetal seizures in patients with epilepsy is likely underestimated, although timely diagnosis of the disease is crucial for patient outcomes.

Study of the role of evolutionary new enhancers in the development of the corpus callosum Исследование роли эволюционно новых энхансеров в развитии мозолистого тела

Modeling epileptic syndromes co-occurring with movement disorders in mice often fails to fully recapitulate human phenotypes due to distinct gene-specific and anatomical mechanisms. This review categorizes these translational barriers into three primary groups. First, ortholog heterotopia and heterochrony drive spatiotemporal shifts in gene expression, causing orthologs to activate at disparate developmental stages or within different cell populations across species. Second, molecular redundancy and compensation obscure phenotypes through the upregulation of alternative proteins in response to target protein suppression, the activation of modifier genes, or neural network rewiring. Third, structural variations in striatal anatomy fundamentally alter corticostriatal loop functioning. Characterizing these divergent mechanisms is essential for improving the predictive validity of preclinical models and advancing targeted therapies.