Developmental and epileptic encephalopathies

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: Sept. 5, 2024

Language: Английский

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Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 181, P. 106094 - 106094

Published: March 27, 2023

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. intrinsic properties thalamic neurons and synaptic between populations nucleus reticularis thalami thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic to highly synchronized burst mode can cause seizures rapidly generalize altered awareness unconsciousness. Here, we review most recent advances our understanding how activity is regulated discuss gaps mechanisms syndromes. Elucidating thalamus syndromes may lead new opportunities better treat pharmaco-resistant by modulation dietary therapy.

Language: Английский

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Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function

Annals of Neurology, Journal Year: 2023, Volume and Issue: 94(5), P. 987 - 1004

Published: Aug. 7, 2023

GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized developmental delay or intellectual disability, hypotonia, movement disorders, epilepsy. Neither a genotype-phenotype correlation nor clear severity score have been established for this disorder. The objective of prospective retrospective observational study was to develop delineate between underlying molecular mechanisms clinical severity.

Language: Английский

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Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1248 - 1248

Published: Jan. 19, 2024

The genetic causes of epilepsies and developmental epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished retrospectively review the clinical, genetic, EEG, neuroimaging, outcome data patients experiencing epilepsy first three years life, diagnosed followed up four Italian centres (Epilepsy Centre San Paolo University Hospital Milan, Child Neurology Psychiatry Unit AUSL-IRCCS di Reggio Emilia, Pediatric Vittore Buzzi Children’s Hospital, Unit, IRCCS Mondino Foundation, Pavia). We included 168 (104 monogenic conditions, 45 copy number variations (CNVs) or chromosomal abnormalities, 19 variants unknown significance), who had been for a mean 14.75 years. found high occurrence generalized seizures at onset, drug resistance, abnormal neurological examination, global delay intellectual disability, behavioural psychiatric comorbidities. also documented differing presentations between issues versus CNVs as well atypical/rare phenotypes. Genetic early-childhood-onset DEE show very wide phenotypic genotypic spectrum, risk complex neuropsychiatric

Language: Английский

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Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1146 - 1146

Published: Jan. 17, 2024

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, seizures accompanied developmental impairment often related to both underlying genetic etiology abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us sequence large portions of DNA quickly with low costs. The aim this study is evaluate the use whole-exome (WES) as a first-line molecular test in sample subjects DEEs early-onset drug-resistant epilepsies, associated global delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants detection rate 43%. identified were highlighted on 29 different genes including, 3 new candidate (KCNC2, STXBP6, DHRS9) for never before. In total, 23 out (66%) de novo identified. most frequently type inheritance was autosomal dominant (60%) followed recessive homozygosity (17%) heterozygosity (11%), inherited from parental mosaicism (6%) X-linked (6%). frequent mutations missense (75%) frameshift deletions (16%), duplications (5%), splicing (3%). Considering results obtained present we support WES form testing DEEs.

Language: Английский

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An update on the seizures beget seizures theory

Epilepsia, Journal Year: 2023, Volume and Issue: 64(S3)

Published: July 19, 2023

Seizures beget seizures is a longstanding theory that proposed seizure activity can impact the structural and functional properties of brain circuits in ways contribute to epilepsy progression future occurrence seizures. Originally by Gowers, this continues be quoted pathophysiology epilepsy. We critically review existing data observations on consequences recurrent networks highlight range factors speak for against theory. The literature demonstrates clearly ictal activity, especially if recurrent, induces molecular, structural, changes including cell loss, connectivity reorganization, neuronal behavior, metabolic alterations. These have potential modify threshold, disease progression, recruit wider areas epileptic network into activity. Repeated may, thus, act as pathological positive-feedback mechanism increases likelihood. On other hand, time course self-limited epilepsies presence remission two thirds cases various chronic models oppose Experimental work showed could induce neural increase threshold decrease risk subsequent seizure. Due complex nature epilepsies, it wrong consider only key factor responsible progression. Epilepsy worsening attributed forms interictal epileptiform or underlying mechanisms. Although negatively structure function, "seizures seizures" should not used dogmatically but with extreme caution.

Language: Английский

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The Neurovascular Unit Dysfunction in the Molecular Mechanisms of Epileptogenesis and Targeted Therapy

Neuroscience Bulletin, Journal Year: 2024, Volume and Issue: 40(5), P. 621 - 634

Published: March 30, 2024

Epilepsy is a multifaceted neurological syndrome characterized by recurrent, spontaneous, and synchronous seizures. The pathogenesis of epilepsy, known as epileptogenesis, involves intricate changes in neurons, neuroglia, endothelium, leading to structural functional disorders within neurovascular units culminating the development spontaneous epilepsy. Although current research on epilepsy treatments primarily centers around anti-seizure drugs, it imperative seek effective interventions capable disrupting epileptogenesis. To this end, comprehensive exploration molecular mechanisms underlying epileptogenesis holds promise identifying vital biomarkers for accurate diagnosis potential therapeutic targets. Emphasizing early timely intervention paramount, stands significantly improve patient prognosis alleviate socioeconomic burden. In review, we highlight unit provide theoretical basis drug

Language: Английский

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Revisiting the concept of drug‐resistant epilepsy: A TASK1 report of the ILAE/AES Joint Translational Task Force

Epilepsia, Journal Year: 2023, Volume and Issue: 64(11), P. 2891 - 2908

Published: Sept. 7, 2023

Abstract Despite progress in the development of anti‐seizure medications (ASMs), one third people with epilepsy have drug‐resistant (DRE). The working definition DRE, proposed by International League Against Epilepsy (ILAE) 2010, helped identify individuals who might benefit from presurgical evaluation early on. As incidence DRE remains high, TASK1 workgroup on ILAE/American Society (AES) Joint Translational Task Force discussed heterogeneity and complexity its presentation mechanisms, confounders drawing mechanistic insights when testing treatment responses, barriers modeling across lifespan translating species. We propose that it is necessary to revisit current order transform preclinical clinical research mechanisms biomarkers, novel, effective, precise, pharmacologic treatments, allowing for earlier recognition drug resistance individualized therapies.

Language: Английский

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Steps to Improve Precision Medicine in Epilepsy

Molecular Diagnosis & Therapy, Journal Year: 2023, Volume and Issue: 27(6), P. 661 - 672

Published: Sept. 27, 2023

Precision medicine is an old concept, but it not widely applied across human health conditions as yet. Numerous attempts have been made to apply precision in epilepsy, this has based on a better understanding of aetiological mechanisms and deconstructing disease into multiple biological subsets. The scope provide effective strategies for treating individual patients with specific agent(s) that are likely work best the causal make-up. We overview main applications including current limitations pitfalls, propose potential implementation achieve higher rate success patient care. Such include establishing definition its outcomes; learning from past experiences, failures other fields (e.g. oncology); using appropriate drug repurposing versus traditional discovery process); adequate methods assess efficacy randomised controlled trials alternative trial designs). Although progress diagnostic techniques now allows comprehensive characterisation each epilepsy condition molecular, biological, structural clinical perspective, there remain challenges integration data practice domain.

Language: Английский

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Long‐term effectiveness and tolerability of ketogenic diet therapy in patients with genetic developmental and epileptic encephalopathy onset within the first 6 months of life

Epilepsia Open, Journal Year: 2024, Volume and Issue: 9(2), P. 643 - 652

Published: Jan. 18, 2024

Abstract Objective To investigate the effectiveness and tolerability of ketogenic diet therapy (KDT) in patients with developmental epileptic encephalopathy (DEE) associated genetic etiology which onset within first 6 months life, to explore association between response KDT genotype/clinical parameters. Methods We retrospectively reviewed data from DEE who started at Beijing Children's Hospital January 1, 2016, December 31, 2021. Results A total 32 were included, involving 14 pathogenic or likely single genes, 16 (50.0%) had sodium/potassium channel gene variants. The median age epilepsy was 1.0 (IQR: 0.1, 3.0) months. initiation 10.0 5.3, 13.8) duration maintenance 14.0 7.0, 26.5) months, a mean blood β‐hydroxybutyrate 2.49 ± 0.62 mmol/L. During period KDT, 26 (81.3%) ≥50% reduction seizure frequency, 12 (37.5%) achieved freedom. Better responses observed STXBP1 variants, four out five achieving There no statistically differences onset, before ketone values, presence ion variants seizure‐free others. most common adverse effects gastrointestinal side effects, occurred 21 (65.6%), but all mild easily corrected. Only one patient discontinued due nephrolithiasis. Significance is effective treating early DEE, significant relationship has been found genotype this study. well tolerated young patients, reversible being common, usually not reason discontinue KDT. Plain Language Summary This study evaluated seizures diagnosed (DEE), type severe delay caused by Thirty‐two included. cohort, responded better; however, variant response. Most well, common.

Language: Английский

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