Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to low-voltage-fast onset seizures in Dravet syndrome

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(23)

Published: May 29, 2024

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities convulsive in patients mouse models Dravet syndrome (DS), a developmental epileptic encephalopathy which hypoexcitability GABAergic neurons considered be the main dysfunction. analyzed EEGs from DS carrying SCN1A pathogenic variant, as well epidural electrocorticograms, hippocampal local field potentials, single-unit neuronal Scn1a +/− RH/+ mice. Strikingly, most had low-voltage-fast onset both mice, thought generated by hyperactivity interneurons, opposite mechanism DS. Analyzing recordings, we observed that temporal disorganization firing putative interneurons period immediately before seizure (preictal) precedes increase their activity at onset, together with entire network. Moreover, found early signatures preictal spectral features cortical potential mice patients’ EEG, are consistent dysfunctions single allowed prediction. Therefore, perturbed leads generalized seizures, similar those other epilepsies triggered neurons. Preictal may used predictive biomarkers.

Language: Английский

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Unveiling the disease progression in developmental and epileptic encephalopathies: Insights from EEG and neuropsychology

Epilepsia, Journal Year: 2024, Volume and Issue: 65(11), P. 3279 - 3292

Published: Sept. 17, 2024

Abstract Objective Developmental and epileptic encephalopathies (DEEs) are neurological disorders characterized by developmental impairment epilepsy. Our study aims to assess disease progression comparing clinical findings, electroencephalography (EEG), neuropsychological data from seizure onset the last follow‐up evaluation. Methods We retrospectively reviewed patients with genetic DEEs who were followed‐up at epilepsy unit of Bambino Gesù Children's Hospital, Rome. collected information regarding gender, family history, variant, age follow‐up, examination, type seizure, drug resistance, occurrence status epilepticus, movement cognitive behavioral disorders. compared EEG background activity, epileptiform abnormalities, functions between evaluation using McNemar‐Bowker test ( α = 5%). Results A total 160 (94 female) included. Genetic analysis revealed a spectrum pathogenic variants, SCN1A being most prevalent (25%). The median was 0.37 (interquartile range [IQR]: 0.09–0.75) 8.54 years (IQR: 4.32–14.55), respectively. documented statistically significant difference in activity p .017) .01) No differences detected for abnormalities .2). In addition, high prevalence rates observed resistance (81.9%), (60.6%), autism (45%), deficits (31.3%), epilepticus (23.1%). Significance provides evidence that may appear DEEs, manifesting as development or worsening disruption activity. These results highlight challenging course importance early intervention personalized care management DEEs.

Language: Английский

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To what extent does status epilepticus contribute to brain damage in the developmental and epileptic Encephalopathies

Epilepsy & Behavior, Journal Year: 2025, Volume and Issue: 164, P. 110271 - 110271

Published: Jan. 29, 2025

Language: Английский

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Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: 207, P. 106853 - 106853

Published: Feb. 26, 2025

Language: Английский

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MOTOR PHENOTYPING IN A GREEK COHORT OF PATIENTS WITH NEONATAL AND INFANTILE ONSET DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY

European Journal of Paediatric Neurology, Journal Year: 2025, Volume and Issue: 55, P. 1 - 8

Published: March 1, 2025

Language: Английский

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PPP5C pathogenic variant identified: a potential key to gaining insight into developmental and epileptic encephalopathy?

Molecular and Cellular Pediatrics, Journal Year: 2025, Volume and Issue: 12(1)

Published: April 2, 2025

Abstract Background Emerging evidence suggesting a possible link between the PPP5C gene (protein phosphatase 5 catalytic subunit; OMIM#600658) and developmental epileptic encephalopathy (DEE, OMIM#308350), although clinical significance of pathogenic variants in this remains unclear. is member protein subunit family, which involved various signaling pathways governing cell growth, differentiation, responses to hormonal signals or cellular stress. To date, only one case with variant has been reported, associated severe neurological phenotype, including microcephaly, failure thrive, early-onset seizures. Results We report 12-year-old girl affected by epilepsy learning disorders. At age five, she presented convulsive status epilepticus respiratory at onset started anticonvulsant therapy Levetiracetam significant improvement. Genetic analysis revealed de novo heterozygous missense (c.202 C > T: p.Arg68Cys ), had not previously described literature. Conclusion This expands phenotypic spectrum variants, highlighting potential role inneurological Our findings may provide some valuable insights into manifestations linked less investigated neuropediatrics.

Language: Английский

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RNF13 Variants L311S and L312P Associated with Developmental Epileptic Encephalopathy Alter Dendritic Organization in Hippocampal Neurons

IBRO Neuroscience Reports, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Identification of a novel homozygous SLC13A5 nonstop mutation in a Chinese family with epileptic encephalopathy and developmental delay

Frontiers in Genetics, Journal Year: 2025, Volume and Issue: 16

Published: April 17, 2025

Biallelic loss-of-function variants in the SLC13A5 (solute carrier family 13, member 5) gene are responsible for autosomal recessive developmental and epileptic encephalopathy 25 with amelogenesis imperfecta (DEE25). Until now, no pathogenic of has been reported among Chinese population. A Han pediatric patient epilepsy global delay was described this study. Trio-whole exome sequencing (WES) including her parents performed to determine genetic basis phenotype. Potential were subsequently confirmed by Sanger sequencing. Additionally, we conducted an extensive review literature regarding analyze their associated phenotypic characteristics. Trio-WES revealed a novel homozygous variant c.1705T>G clinical manifestations proband. The also detected unaffected sister, who both heterozygous carriers. is nonstop substitution that predicted extend protein 174 amino acids (p.569Gluext174). Analysis previously published cases indicated our study exhibited overlapping symptoms. We identified mutation DEE25. This expands spectrum will have significant implications proband's terms medical management counseling.

Language: Английский

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Voltage‐gated sodium channels in genetic epilepsy: up and down of excitability

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 168(12), P. 3872 - 3890

Published: Aug. 31, 2023

Abstract The past two decades have witnessed a wide range of studies investigating genetic variants voltage‐gated sodium (Na V ) channels, which are involved in broad spectrum diseases, including several types epilepsy. We reviewed here phenotypes and pathological mechanisms epilepsies caused by Na α β subunits, as well some relevant interacting proteins ( FGF12/FHF1 , PRRT2, Ankyrin‐G). Notably, all these genes can induce either gain‐ or loss‐of‐function leading to neuronal hyperexcitability hypoexcitability. present the results functional obtained with different experimental models, highlighting that they should be interpreted considering features system used. These systems but allowed us better understand pathophysiological issues, ameliorate diagnostics, orientate counseling, select/develop therapies within precision medicine framework. also gain insights into physiological roles channels cells express them. Overall, our review shows progress has been made, need for further on aspects not yet clarified. Finally, we conclude significant themes general interest gleaned from work last decades. image

Language: Английский

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Providing quality care for people with CDKL5 deficiency disorder: A European expert panel opinion on the patient journey

Epilepsia Open, Journal Year: 2024, Volume and Issue: 9(3), P. 832 - 849

Published: March 7, 2024

Abstract Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy caused by variants in the CDKL5 gene. The characterized intractable early‐onset seizures, severe neurodevelopmental delay, hypotonia, motor disabilities, cerebral (cortical) visual impairment microcephaly. With no disease‐modifying therapies available for CDD, treatment symptomatic with an initial focus on seizure control. Another unmet need management of people CDD lack evidence to aid standardized care guideline development. To address this gap, experts representatives from patient advocacy groups Denmark, Finland, France, Germany, Italy, Poland, Spain, United Kingdom convened form Expert Working Group. aim was provide expert opinion consensus how ensure quality routine clinical practice within European setting, including settings limited experience or resources multidisciplinary other encephalopathies. By means one‐to‐one interviews around current landscape insights Group were collated developed into Europe‐specific journey individuals which later validated group. Further discussions followed gain opinions challenges potential solutions achieving setting. panel recognized benefit early genetic testing, holistic personalized approach control (taking consideration various factors such as concomitant medications comorbidities), age‐ comorbidity‐dependent optimizing outcomes life. However, their experiences also highlighted much disparity approaches across different countries. Development recommendations required align realistic diagnostic criteria, goals, that can be adapted settings. Plain language summary rare condition mutation broad range symptoms apparent childhood, seizures do not respond medication delays Due guidance managing international advocates discussed best practices Europe. agreed access disciplines are beneficial. guidelines would valuable.

Language: Английский

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