International Journal of Molecular Sciences

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Dr. Christalena Sofocleous

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Laboratory of Medical Genetics, School of Medicine, National & Kapodistrian University of Athens, “St. Sophia’s Childrens Hospital”, 11527 Athens, Greece
Interests: molecular investigation of neurodevelopmental disorders; epigenetics

Special Issue Information

Dear Colleagues,

Causes of epilepsy, the most common neurological condition worldwide, include hypoxia, ischemia, CNS infection, or brain injury, as well as genetic causes, such as chromosomal anomalies (trisomy 21 or ring chromosome 20), monogenic neurodevelopmental disorders (fragile X, Rett, and Angelman syndromes), and causative, usually de novo, variants in genes implicated in neuronal function. Epilepsy syndromes may be classified according to the age of onset (neonatal–infantile, childhood, and variable), the seizure semiology, and the underlying pathogenic mechanism (channelopathies, synaptopathies, and interneuronopathies). Advancing technologies keep revealing novel epileptogenic mechanisms, such as neurodegeneration, defects in the neuronal crest, cytoskeleton organization and chromatin modification, cellular interference, and the accumulation of toxic products, in addition to new correlations with causative genetic defects in novel genes.

Molecular genetic testing for diagnoses currently employs next-generation sequencing applications towards the detection and characterization of (likely) pathogenic variants. A definitive diagnosis enables trial recruitment as well as enrollment, and optimized, even personalized, medical management, whereby specific medications may be selected or excluded.

The focus of this Special Issue on the molecular diagnostics and therapeutics of epileptic neurodevelopment calls for submissions on findings that will further expand our knowledge on the mechanisms underlying the development of epilepsy. The discovery and characterization of genetic and epigenetic factors linked to epileptogenesis are constant and expected to provide novel insights to the scientific community. In light of novel findings and the emerging genetically based therapeutic procedures, manuscripts of all kinds (original research reports, reviews, perspectives/opinions, and methodologies) are most welcome and anticipated to showcase the importance of molecular diagnostics when studying epileptic neurodevelopment.

Dr. Christalena Sofocleous
Guest Editor

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Keywords

epileptic neurodevelopment
molecular diagnostics
next-generation sequencing
genetics
epigenetics
pathogenic/likely pathogenic variants
therapeutics

Published Papers (2 papers)

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Research

18 pages, 1514 KiB

Open AccessArticle

SCN1A Channels a Wide Range of Epileptic Phenotypes: Report of Novel and Known Variants with Variable Presentations

by Danai Veltra, Virginia Theodorou, Marina Katsalouli, Pelagia Vorgia, Georgios Niotakis, Triantafyllia Tsaprouni, Roser Pons, Konstantina Kosma, Afroditi Kampouraki, Irene Tsoutsou, Periklis Makrythanasis, Kyriaki Kekou, Joanne Traeger-Synodinos and Christalena Sofocleous

Int. J. Mol. Sci. 2024, 25(11), 5644; https://doi.org/10.3390/ijms25115644 - 22 May 2024

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Abstract

SCN1A, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel’s function affect the initiation and propagation of action potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation of SCN1A channelopathy, is characterized by severe myoclonic epilepsy in infancy (SMEI). Variants’ characteristics and other genetic or epigenetic factors lead to extreme clinical heterogeneity, ranging from non-epileptic conditions to developmental and epileptic encephalopathy (DEE). This current study reports on findings from 343 patients referred by physicians in hospitals and tertiary care centers in Greece between 2017 and 2023. Positive family history for specific neurologic disorders was disclosed in 89 cases and the one common clinical feature was the onset of seizures, at a mean age of 17 months (range from birth to 15 years old). Most patients were specifically referred for SCN1A investigation (Sanger Sequencing and MLPA) and only five for next generation sequencing. Twenty-six SCN1A variants were detected, including nine novel causative variants (c.4567A>Τ, c.5564C>A, c.2176+2T>C, c.3646G>C, c.4331C>A, c.1130_1131delGAinsAC, c.1574_1580delCTGAGGA, c.4620A>G and c.5462A>C), and are herein presented, along with subsequent genotype–phenotype associations. The identification of novel variants complements SCN1A databases extending our expertise on genetic counseling and patient and family management including gene-based personalized interventions. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutics of Epileptic Neurodevelopment)

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15 pages, 3717 KiB

Open AccessArticle

Enhanced Astrocyte Activity and Excitatory Synaptic Function in the Hippocampus of Pentylenetetrazole Kindling Model of Epilepsy

by Franco Díaz, Freddy Aguilar, Mario Wellmann, Andrés Martorell, Camila González-Arancibia, Lorena Chacana-Véliz, Ignacio Negrón-Oyarzo, Andrés E. Chávez, Marco Fuenzalida, Francisco Nualart, Ramón Sotomayor-Zárate and Christian Bonansco

Int. J. Mol. Sci. 2023, 24(19), 14506; https://doi.org/10.3390/ijms241914506 - 25 Sep 2023

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Abstract

Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca²⁺ activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca²⁺-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte–neuron interactions are pivotal mechanisms in epileptogenesis. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutics of Epileptic Neurodevelopment)

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