GRIA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy

Synaptic AMPA Receptor Plasticity and Behavior

Novel compound heterozygous P4HTM variants in a girl with developmental and epileptic encephalopathy: First case report of P4HTM variant-associated epileptic encephalopathy

Developmental encephalopathies, including intellectual disability and autistic spectrum disorder, are frequently associated with infant epilepsy. Epileptic encephalopathy is used to describe an assumed causal relationship between epilepsy and developmental delay. Developmental encephalopathies pathogenesis more independent from epilepsy is supported by the identification of several gene variants associated with both developmental encephalopathies and epilepsy, the possibility for gene-associated developmental encephalopathies without epilepsy, and the continued development of developmental encephalopathies even when seizures are controlled. Hence, 'developmental and epileptic encephalopathy' may be a more appropriate term than epileptic encephalopathy. This update considers the best studied 'developmental and epileptic encephalopathy' gene variants for illustrative support for 'developmental and epileptic encephalopathy' over epileptic encephalopathy. Moreover, the interaction between epilepsy and developmental encephalopathies is considered with respect to influence on treatment decisions. Continued research in genetic testing will increase access to clinical tests, earlier diagnosis, better application of current treatments, and potentially provide new molecular-investigated treatments.

Semi-quantitative analyses of antibodies to N-methyl-d-aspartate type glutamate receptor subunits (GluN2B & GluN1) in the clinical course of Rasmussen syndrome

Coupled Control of Desensitization and Gating by the Ligand Binding Domain of Glutamate Receptors

Chapter 14 - Developmental and epileptic encephalopathies

Off-label use of cannabidiol in genetic epileptic and developmental encephalopathies: A case report

SCN1A-related diseases are a heterogeneous group of disorders with an expanding spectrum of phenotypes. Until recently, mutations in this gene were associated with epileptic syndromes and epileptic and developmental encephalopathy – Dravet syndrome, which was contrasted with a new group of early-onset syndromes, non-Dravet developmental and epileptic encephalopathies (DEEs; OMIM: PS308350). The aim of this paper is to review published data on the phenotypic variability of SCN1A-related developmental and epileptic encephalopathies, particularly non-Dravet syndromes. These are disorders with very early onset, polymorphic, drug-resistant epileptic seizures, impaired psychomotor development and intellectual disability, as well as the presence of additional symptoms such as arthrogryposis, osteopenia, and hyperkinetic movement disorders. Unlike Dravet syndrome, epileptic seizures begin in the first few months of life and may have an epileptic spasm or tonic morphology. The ability to quickly recognise the non-Dravet developmental and epileptic encephalopathy is of significant clinical value, because the identification of pathogenic SCN1A variants and their functional evaluation have an impact on both treatment and prognosis. Studies on the aetiology of non-Dravet developmental and epileptic encephalopathies have shown that pathogenic variants of the gain of function (GOF) type are identified in these patients. Therefore, it is possible to treat such patients with medicaments from the group of sodium channel blockers, which were contraindicated in cases of loss of function (LOF) variants, occurring in Dravet syndrome.

Metabolic causes of pediatric developmental & epileptic encephalopathies (DEE)- genetic variant analysis in a south Indian cohort

Introduction. The problem of early diagnostics of orphan diseases is relevant for most countries of the world. The challenge for healthcare is to prevent new cases of orphan diseases by providing medical genetic testing and counseling at the stage of family planning. Department of psychoneurology of the State Intstitution "Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova National Academy of Medical Sciences of Ukraine" has been dealing with the problem of orphan diseases since 2012 and has significant experience in their diagnosis and treatment in children.The aim of paper: to develop an algorithm for the genetic diagnosis of epileptic and developmental encephalopathies in children with developmental delay and dimorphic features based on modern data on the application and interpretation of genetic methods. A case which demonstrate the complexity of interpreting the results and algorithms for early diagnosis of patients and the importance of medical and genetic counseling is presentedMaterial and methods: clinical and neurological examination, sleep video-EEG monitoring during night sleep, brain magnetic resonance imaging (3.0T), whole-exome sequencing (WES).Results. The article presents the algorithm of genetic diagnosis of orphan diseases in children with developmental and epileptic encephalopathies, developmental delay, and dimorphic features. A clinical case of a boy with general developmental delay and atonic epileptic seizures is presented. Sleep EEG-monitoring showed epileptiform activity in the stage of slow-wave sleep localized in the central-parietal and left temporal areas in the form of benign childhood epileptiform patterns.Whole-exome sequencing detected a variant of uncertain significance (VUS) c.5887C>T(p.Arg1963Cys) of SON gene in a heterozygous state, which leads to the replacement of arginine to cysteine. Mutations in the SON gene in the heterozygous state have been described in patients with Zhu-Tokita-Takenouchi-Kim syndrome (OMIM: 617140).Conclusions: It is important for pediatricians and neurologists to be aware of orphan diseases in children with developmental and epileptic encephalopaties and developmental delay. Genetic tests are wide available but they require competent interpretation by clinicists. After obtaining the results, it is important to compare the obtained result with the phenotype of patient. In case the phenotype of patient match and the results of genetic test, (detected VUS) this mutation could be etiological factor of the disease. In our case, the clinical signs coincided with those described in 2015 by the authors of the first description of Zhu-Tokita-Takenuchi-Kim syndrome, and therefore genetic testing helped to verify the final diagnosis. Therefore genetic counseling is extremely important for detection of etiology and prognosis of early developmental and epileptic encephalopathies/

HNK-1 (human natural killer-1) glyco-epitope, a sulfated glucuronic acid attached to N-acetyllactosamine on the nonreducing termini of glycans, is highly expressed in the nervous system. Our previous report showed that mice lacking a glucuronyltransferase (GlcAT-P), a key enzyme for biosynthesis of the HNK-1 epitope, showed reduced long term potentiation at hippocampal CA1 synapses. In this study, we identified an alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA)-type glutamate receptor subunit, GluR2, which directly contributes to excitatory synaptic transmission and synaptic plasticity, as a novel HNK-1 carrier molecule. We demonstrated that the HNK-1 epitope is specifically expressed on the N-linked glycan(s) on GluR2 among the glutamate receptors tested, and the glycan structure, including HNK-1 on GluR2, was determined using liquid chromatography-tandem mass spectrometry. As for the function of HNK-1 on GluR2, we found that the GluR2 not carrying HNK-1 was dramatically endocytosed and expressed less on the cell surface compared with GluR2 carrying HNK-1 in both cultured hippocampal neurons and heterologous cells. These results suggest that HNK-1 stabilizes GluR2 on neuronal surface membranes and regulates the number of surface AMPA receptors. Moreover, we showed that the expression of the HNK-1 epitope enhanced the interaction between GluR2 and N-cadherin, which has important roles in AMPA receptor trafficking. Our findings suggest that the HNK-1 epitope on GluR2 regulates cell surface stability of GluR2 by modulating the interaction with N-cadherin.

<h3>Objective:</h3> To investigate the landscape of clinical outcome assessments (COAs) used in epileptic encephalopathies (EEs) and developmental epileptic encephalopathies (DEEs). <h3>Background:</h3> EEs and DEEs are rare conditions characterized by difficult-to-treat seizures and intellectual or developmental disability. The heterogeneity of these conditions creates unique challenges for outcome measurement, particularly in clinical trials. To assess trends in the COA landscape, a targeted literature review was conducted to identify COAs used in EE and DEE clinical trials. <h3>Design/Methods:</h3> A search was conducted in ClinicalTrials.gov to identify interventional studies in EEs and DEEs. Findings were supplemented by searches in PubMed (titles/abstracts only), PROLABELS, and Food and Drug Administration (FDA) COA guidance materials, pairing EE/DEE and COA search terms when applicable. No limits on year of publication were applied. All results were reviewed, and relevant data were extracted and analyzed to identify trends in COA use. <h3>Results:</h3> The search identified 153 trials (ClinicalTrials.gov), 405 articles (PubMed), and 92 FDA drug labels (PROLABELS). Following screening, 105 trials, 26 article abstracts, and 19 labels met the criteria for data extraction. Excluding safety measures, 113 COAs were identified. Consistent with FDA guidance, seizure assessments and diaries were utilized most frequently, followed by clinician- or caregiver-rated global impression measures. Observer-reported outcomes and clinician-reported outcomes were more common than patient-reported outcomes. Approximately 25% of COAs were disease-specific. Additionally, common domains in COAs reviewed included cognition (n=22), motor functioning (n=14), multi-domains or quality of life (n=14), or communication (n=6). Several COAs utilized a global impression approach to assess within-patient change in domains, such as seizure severity or non-seizure concepts. <h3>Conclusions:</h3> Importantly, disease-specific measures, including global impression items intended to capture change in multiple domains, were identified. These findings may suggest that a disease-specific global impression approach is becoming increasingly common in these heterogeneous conditions to accompany seizure assessments and diaries. <b>Disclosure:</b> Ms. Graham has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of IQVIA. Dr. Chladek has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of Clinical Outcomes Solutions. Ms. Nacson has received personal compensation for serving as an employee of IQVIA. Dr. Batchelder has received personal compensation for serving as an employee of IQVIA. Dr. Gleeson has nothing to disclose. Ms. Buenfil has received personal compensation for serving as an employee of IQVIA. Ms. Kim has received personal compensation for serving as an employee of IQVIA. Dr. Meyers has received personal compensation for serving as an employee of IQVIA. Dr. Williams has received personal compensation for serving as an employee of IQVIA.

IntroductionFenfluramine (FFA) represents the latest therapeutic option approved for seizure management in Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) for patients aged ≥ 2 years. This article provides expert guidance for optimizing FFA therapy to support clinical decision-making in these populations.MethodsA panel of Spanish experts specialized in developmental epileptic encephalopathies (DEEs) has developed practical recommendations for the clinical use of FFA, focusing on key aspects of FFA management: mechanism of action, pharmacokinetics including drug interactions, titration, efficacy, safety and tolerability, contraindications, and considerations for its broader application in DEEs. The methodology adopted in this project was an expert-opinion, evidence-based approach.ResultsThe panel issued targeted recommendations, including a modified titration strategy slower than the product guidelines, adjusted for possible antiseizure concomitant medications, and management of other concomitant treatments. Key efficacy indicators, such as reductions in seizure frequency and severity of the most disabling seizures, were emphasized as core measures for treatment evaluation. Periodic assessments of non-seizure outcomes and daily life activities are recommended during follow-up to comprehensively capture treatment outcomes. The panel noted that their clinical observations align with positive findings from clinical trials, suggesting a potential role for FFA in other DEEs, tailored to individual electroclinical and etiological profiles.ConclusionThis article presents expert practical recommendations for the management and treatment optimization of FFA in patients with DEEs, supporting clinicians in achieving improved patient outcomes.

High-dose diazepam as a long-term treatment strategy for epileptic encephalopathy and developmental epileptic encephalopathy spike-and-wave activation in sleep: A tertiary center's experience.

Developmental epileptic encephalopathy is characterized by a malignant course of refractory epilepsy and a growing defect in mental and motor development. To date, determinant genes have been identified for most of these conditions. This condition is also caused by mutations in the SCN8A gene of a voltage-gated sodium channel, which is detected in about 1% of children with early infantile epileptic encephalopathies. SCN8A gene mutations result in both an increase (gain-of-function, GOF mutation) and a decrease (loss-of-function, LOF mutation) in NaV1.6 sodium channel function, leading to a decrease in current amplitude and a depolarizing shift. With GOF mutation, hypotension, cerebral visual dysfunction, dyskinesia, ataxia, and epileptic seizures are mainly present as bilateral tonic and focal seizures and, in most cases, lead to epileptic encephalopathy. With the LOF mutation, seizures (absences, bilateral tonic-clonic myoclonic seizures) may not appear, while cognitive impairment, movement disorders, and autistic traits are present. Anticonvulsant regimens include non-selective sodium channel blockers, GABA agonists, Na+ and Ca2+ channel blockers, and other agents. A specific feature of the phenotype is a relatively high probability of exacerbation of the epilepsy during anticonvulsant selection, which requires special care and caution from the doctor. As an illustration of the most typical features of the condition, a clinical case of severe refractory epilepsy with a developmental disorder in an infant is presented. The disease progressed despite all attempts to select therapy. Treatment with corticosteroids gave a temporary effect, and when the drug was discontinued, the frequency and severity of seizures increased, suggesting the GOF scenario; however, genetic confirmation was inaccessible. The authors believe that the prospects for treating such conditions are determined primarily by progress in the development of new drugs, including oligonucleotides and selective inhibitors of NaV1.6 channels.