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Pathogenic variants in the cyclin‐dependent kinase‐like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X‐linked developmental and epileptic encephalopathy. Deletions affecting the 5′ untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a–e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5′ UTR. All individuals presented characteristic features of CDD, including medically refractory infantile‐onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5′ UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5′ UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity. [ABSTRACT FROM AUTHOR]

Developmental delay and seizures with or without movement abnormalities (DEDSM) is a neurodevelopmental phenotype associated with monoallelic mutations in the DHDDS gene. We report a novel case of DEDSM linked to a DHDDS variant (c.614G > A, p.Arg205Gln) in a 45-year-old Brazilian patient presenting with refractory epilepsy, ataxia, dystonia, parkinsonism, and global developmental delay. This is the first case to associate a DHDDS variant with hippocampal atrophy on neuroimaging. After adjustments in anticonvulsant therapy, seizure control was achieved, and the patient—who was previously unable to walk due to frequent falls attributed to myoclonic jerks—showed significant improvement in gait and mobility. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance SCN2A encodes the voltage‐gated sodium (Na+) channel α subunit NaV1.2, which is important for the generation and forward and back propagation of action potentials in neurons. Genetic variants in SCN2A are associated with a spectrum of neurodevelopmental disorders. However, the mechanisms whereby variation in SCN2A leads to disease remains incompletely understood, and the full spectrum of SCN2A‐related disorders may not be fully delineated.Here, we identified seven de novo heterozygous variants in SCN2A in eight individuals with developmental and epileptic encephalopathy (DEE) accompanied by prominent malformation of cortical development (MCD). We characterized the electrophysiological properties of Na + currents in human embryonic kidney (HEK) cells transfected with the adult (A) or neonatal (N) isoform of wild‐type (WT) and variant NaV1.2 using manual and automated whole‐cell voltage clamp recording.The neonatal isoforms of all SCN2A variants studied exhibit gain of function (GoF) with a large depolarized shift in steady‐state inactivation, creating a markedly enhanced window current common across all four variants tested. Computational modeling demonstrated that expression of the NaV1.2‐p.Met1770Leu‐N variant in a developing neocortical pyramidal neuron results in hyperexcitability.These results support expansion of the clinical spectrum of SCN2A‐related disorders and the association of genetic variation in SCN2A with MCD, which suggests previously undescribed roles for SCN2A in fetal brain development. [ABSTRACT FROM AUTHOR]

Pathogenic variation in HCN1 is now an established cause of epilepsy and intellectual disability. Variation in HCN1 causes a spectrum of disease with a genotype–phenotype relationship emerging. De novo pathogenic variants that occur in the transmembrane domains of the channel typically cause a cation 'leak' that associates with severe developmental and epileptic encephalopathy (DEE). Genotype–phenotype associations for variants that fall outside of the transmembrane domains are less well established but do include milder forms of epilepsy that can be either de novo or inherited. HCN1 DEE mouse models have been generated which recapitulate the seizures and learning difficulties seen in human patients. These mice have also acted as powerful preclinical models which share pharmacoresponsiveness with human HCN1 DEE patients. Data from these mouse models support the conclusion that anti‐seizure medications with sodium channel block as their primary mechanism of action should be used with caution in HCN1 DEE. Other comorbidities of HCN1 DEE including retinal dysfunction have also been modelled in HCN1 DEE mice, suggesting HCN1 variants can cause a dramatically reduced sensitivity to light with limited ability to process temporal information. Our understanding of the genetics and pathophysiological mechanisms underlying HCN1 epilepsy has progressed significantly and is already influencing therapy. However, more research effort is needed to fully understand the natural histories of HCN1 epilepsies and to develop precision therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective: EEG patterns and quantitative EEG (qEEG) features have been poorly explored in monogenic epilepsies. Herein, we investigate regional differences in EEG frequency composition in patients with STXBP1 developmental and epileptic encephalopathy (STXBP1‐DEE). Methods: We conducted a retrospective study collecting electroclinical data of patients with STXBP1‐DEE and two control groups of patients with DEEs of different etiologies and typically developing individuals matched for age and sex. We performed a (1) visual EEG assessment, (b) qEEG analysis, and (c) electrical source imaging (ESI). We quantified the relative power (RP) of four frequency bands (α β, θ, δ), in two electrode groups (anterior/posterior), and compared their averages and dynamics (standard deviation [SD] over time). The ESI was performed by applying the standard Distributed Source Modeling algorithm. Results: We analyzed 42 EEG studies in 19 patients with STXBP1‐DEE (10 female), with a median age at recordings of 9.6 years (range 9 months to 29 years). The δRP was higher in recordings of STXBP1‐DEE (p <.001) compared to both control groups, suggesting the pathogenicity and STXBP1‐specificity of these findings. In STXBP1‐DEE, the δRP was significantly higher in the anterior electrode group compared to the posterior one (p =.003). There was no correlation between the anterior δRP and the epilepsy focus, age at recordings, and concomitant medications The ESI modeling of this activity showed a widespread involvement of the dorsomesial frontal cortex, suggesting a large corticosubcortical pathologic network. Finally, we identified two groups of recordings: cluster.1 with higher anterior δRP and low dynamics and cluster.2 with lower δRP and higher dynamics. Patients in cluster.1 had a more severe epilepsy and neurological phenotype compared to patients in cluster 2. Significance: The qEEG analysis showed a predominant frontal slow activity as a specific STXBP1 feature that correlates with the severity of the phenotype and may represent a biomarker for prospective longitudinal studies of STXBP1‐DEE. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a life‐threatening emergency with high morbidity and mortality. In people with epilepsy, the management of SE is focused on early medical treatment. Stiripentol is a third‐generation antiseizure medication (ASM) approved for refractory generalized tonic–clonic seizures in Dravet syndrome. The aim of this systematic review was to evaluate the effectiveness and safety of stiripentol in reducing the incidence of SE in patients with Dravet syndrome or any epilepsy characterized by recurrent SE. The PubMed and Cochrane databases were systematically searched, and gray literature was hand‐searched. Search results were screened by title and abstract; studies with data on the effect of stiripentol on SE outcomes, including the cessation of SE, reduction in number of SE episodes, or reduction in hospitalizations, were included. Of 66 records identified, 17 studies were eligible for inclusion, of which 15 were human studies (n = 474; aged 1.1–78 years), and two were animal experiments. Results of retrospective or prospective observational studies showed that stiripentol as add‐on therapy to ASMs such as clobazam or valproate reduced the incidence of SE in patients with Dravet syndrome or other developmental and epileptic encephalopathies (DEEs). A mean of 68% of patients (range 41%–100%) had a ≥50% reduction in SE episodes from baseline, and 26%–100% of patients (mean 77%) became SE‐free after stiripentol initiation. Moreover, this review found stiripentol, used as acute treatment, may also be effective for the cessation of super‐refractory SE, but data are limited to three retrospective case series. Stiripentol was generally well‐tolerated. In conclusion, stiripentol reduces the incidence of SE episodes in patients with Dravet syndrome and potentially other DEEs, and it promotes cessation of super‐refractory SE in patients with and without a history of seizures. Plain Language Summary: Status epilepticus (SE) is a life‐threatening, long‐lasting seizure occurring in patients with/without epilepsy. This article analyzed 15 published studies that investigated the effects and safety of the anti‐seizure medication stiripentol for preventing SE in epilepsy patients (prevention) or stopping an SE episode (cessation), and two animal studies that investigated how stiripentol works. In epilepsy patients, stiripentol halved the number of SE episodes in 41–100% of patients, 26–100% of patients became SE‐free, and stiripentol was considered to be well tolerated. In patients with/without epilepsy, stiripentol may stop the SE episode after other drugs like anesthetics have not worked. [ABSTRACT FROM AUTHOR]

Background: The TSC1 gene encodes a growth inhibitory protein hamartin, which plays a crucial role in negative regulation of the activity of mTORC1 (mechanistic target of rapamycin complex 1). TSC1 has been associated with tuberous sclerosis complex (TSC). This study aims to investigate the association between TSC1 variants and common epilepsy. Methods: Trio-based whole-exome sequencing was performed in epilepsy patients without acquired etiologies from the China Epilepsy Gene 1.0 Project platform. The pathogenicity of the variants was evaluated according to the American College of Medical Genetics and Genomic (ACMG) guidelines. Results: Two TSC1 de novo variants, including c.1498 C > T/p.Arg500* and c.2356 C > T/p.Arg786*, were identified in two patients with developmental and epileptic encephalopathy (DEE). The patients exhibited frequent seizures and neurodevelopmental delay. Additionally, we identified two heterozygous TSC1 variants that affected four individuals with focal epilepsy from two unrelated families. The four probands did not present any typical symptom of TSC and had normal brain MRI findings. The four variants were absent in the Genome Aggregation Database (gnomAD) and were predicted to be damaging with a in silico prediction tool. Based on the ACMG guidelines, the four variants were evaluated to be "pathogenic" or "likely pathogenic". Of the patients in the China Epilepsy Gene 1.0 Project, 22 patients carried TSC1 variants and were diagnosed with TSC. The ratio of patients carrying TSC1 variants with or without TSC is about 5:1. Conclusions: TSC1 is potentially associated with common epilepsy without tuberous sclerosis. [ABSTRACT FROM AUTHOR]

WWOX developmental and epileptic encephalopathy is characterised by drug-resistant epilepsy with onset within the first year of life and severe psychomotor developmental delay. This report presents for the first time a clinical case of an adult patient with a homozygous likely pathogenic variant (p.Thr12Met) in the WWOX gene, with more than 40 years of follow-up. The patient had refractory epilepsy with various types of seizures during his life: mainly epileptic spasms, autonomic, myoclonic, tonic seizures, and absences. The patient had a prominent developmental delay with a lack of expressive speech, but by the age of 3, he had acquired the skills to sit, crawl, and walk with support. In adolescence, there was an acute regression of acquired skills to a total absence of independent motor activity. The patient had dysmorphic features, such as upslanting palpebral fissures, arched eyebrows, and hypertelorism. For many years, the patient was given a diagnosis of cerebral palsy; 38 years after the onset of the disease, he was given a molecular genetic diagnosis of WWOX -associated developmental and epileptic encephalopathy. Our observation illustrates the natural history of WWOX -DEE and the high clinical significance of early genetic diagnostics for identifying the cause of developmental delay and resistant epilepsy. [ABSTRACT FROM AUTHOR]

Copyright of Clinical Epileptology / Zertifizierte Fortbildung is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Status epilepticus (SE) is a life‐threatening emergency with high morbidity and mortality. In people with epilepsy, the management of SE is focused on early medical treatment. Stiripentol is a third‐generation antiseizure medication (ASM) approved for refractory generalized tonic–clonic seizures in Dravet syndrome. The aim of this systematic review was to evaluate the effectiveness and safety of stiripentol in reducing the incidence of SE in patients with Dravet syndrome or any epilepsy characterized by recurrent SE. The PubMed and Cochrane databases were systematically searched, and gray literature was hand‐searched. Search results were screened by title and abstract; studies with data on the effect of stiripentol on SE outcomes, including the cessation of SE, reduction in number of SE episodes, or reduction in hospitalizations, were included. Of 66 records identified, 17 studies were eligible for inclusion, of which 15 were human studies (n = 474; aged 1.1–78 years), and two were animal experiments. Results of retrospective or prospective observational studies showed that stiripentol as add‐on therapy to ASMs such as clobazam or valproate reduced the incidence of SE in patients with Dravet syndrome or other developmental and epileptic encephalopathies (DEEs). A mean of 68% of patients (range 41%–100%) had a ≥50% reduction in SE episodes from baseline, and 26%–100% of patients (mean 77%) became SE‐free after stiripentol initiation. Moreover, this review found stiripentol, used as acute treatment, may also be effective for the cessation of super‐refractory SE, but data are limited to three retrospective case series. Stiripentol was generally well‐tolerated. In conclusion, stiripentol reduces the incidence of SE episodes in patients with Dravet syndrome and potentially other DEEs, and it promotes cessation of super‐refractory SE in patients with and without a history of seizures. Plain Language Summary Status epilepticus (SE) is a life‐threatening, long‐lasting seizure occurring in patients with/without epilepsy. This article analyzed 15 published studies that investigated the effects and safety of the anti‐seizure medication stiripentol for preventing SE in epilepsy patients (prevention) or stopping an SE episode (cessation), and two animal studies that investigated how stiripentol works. In epilepsy patients, stiripentol halved the number of SE episodes in 41–100% of patients, 26–100% of patients became SE‐free, and stiripentol was considered to be well tolerated. In patients with/without epilepsy, stiripentol may stop the SE episode after other drugs like anesthetics have not worked.

Abstract Objective To develop a high‐throughput sequencing panel for the diagnosis of developmental and epileptic encephalopathy in Tunisia and to clarify the frequency of disease‐causing genes in this region. Methods We developed a custom panel for next‐generation sequencing of the coding sequences of 116 genes in individuals with developmental and epileptic encephalopathy from the Tunisian population. Segregation analyses and in silico studies have been conducted to assess the identified variants' pathogenicity. Results We report 12 pathogenic variants in SCN1A, CHD2, CDKL5, SZT2, KCNT1, GNAO1, PCDH19, MECP2, GRIN2A, and SYNGAP1 in patients with developmental and epileptic encephalopathy. Five of these variants are novel: “c.149delA, p.(Asn50MetfsTer26)” in CDKL5; “c.3616C > T, p.(Arg1206Ter)” in SZT2; “c.111_113del, p.(Leu39del)” in GNAO1; “c.1435G>C, p.(Asp479His)” in PCDH19; and “c.2143delC, p.(Arg716GlyfsTer10)” in SYNGAP1. Additionally, for four of our patients, the genetic result facilitated the choice of the appropriate treatment. Significance This is the first report of a custom gene panel to identify genetic variants implicated in developmental and epileptic encephalopathy in the Tunisian population as well as the North African region (Tunisia, Egypt, Libya, Algeria, Morocco) with a diagnostic rate of 30%. This high‐throughput sequencing panel has considerably improved the rate of positive diagnosis of developmental and epileptic encephalopathy in the Tunisian population, which was less than 15% using Sanger sequencing. The benefit of genetic testing in these patients was approved by both physicians and parents.

Abstract Objective KCNT1‐related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep‐related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug‐resistant seizures and global developmental delays. In addition to conventional anti‐seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD—including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients. Methods We performed a literature review on PubMed and EMBase with the keyword “KCNT1” and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype. Results A total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%–25% of patients). Significance Ketogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug‐resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1‐related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors. Plain Language Summary We performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti‐seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion.

Abstract Background Developmental and Epileptic Encephalopathies (DEEs) are defined by drug-resistant seizures and neurodevelopmental disorders. Over 50% of patients have a genetic cause. Studies have shown that patients with DEEs, regardless of genetic diagnosis, experience a central visual function disorder known as Cerebral (cortical) Visual Impairment (CVI). The prevalence of CVI in DEE patients is currently unknown. A quantitative synthesis of existing data on the prevalence rates of this condition would aid in understanding the magnitude of the problem, outlining future research, and suggesting the need for therapeutic strategies for early identification and prevention of the disorder. Methods The protocol followed the PRISMA-P statement for systematic review and meta-analysis protocols. The review will adhere to the JBI Manual for Evidence Synthesis (Systematic Reviews of Prevalence and Incidence) and use the CoCoPop framework to establish eligibility criteria. We will conduct a comprehensive search of several databases, including MEDLINE, EMBASE, Science Direct, Scopus, PsychINFO, Wiley, Highwire Press, and Cochrane Library of Systematic Reviews. Our primary focus will be determining the prevalence of cerebral visual impairments (Condition) in patients with developmental and epileptic encephalopathy (Population). To ensure clarity, we will provide a narrative summary of the risk of bias in the studies we include. The Cochrane Q statistic will be used to assess heterogeneity between studies. If the quantitative synthesis includes more than 10 studies, potential sources of heterogeneity will be investigated through subgroup and meta-regression analyses. Meta(bias)es analysis will also be performed. The quality of evidence for all outcomes will be evaluated using the Grading of Recommendations Assessment Development and Evaluation (GRADE) working group methodology. Discussion This protocol outlines a systematic review and meta-analysis to identify, collect, evaluate, and integrate epidemiological knowledge related to the prevalence of CVI in patients with DEEs. To the best of our knowledge, no other systematic review and meta-analysis has addressed this specific issue. The results will provide useful information for understanding the extent of the problem, outlining future research, and suggesting the need for early identification strategies. Systematic review registrations This Systematic Review Protocol was registered in PROSPERO (CRD42023448910).

• Our study unravels distinct clinical trajectories associated with PPP3CA mutations, from early-onset severe phenotypes to late-onset moderate forms, emphasizing the critical influence of mutation location within the gene on the severity of developmental and epileptic encephalopathy. • Corroborating the existing literature, our cases reaffirm the correlation between the degree of protein loss of function and the severity of PPP3CA-related DEE: missense mutations associate with milder phenotypes, while truncating mutations lead to profound disabilities and potentially fatal outcomes. • Beyond seizure types, our study meticulously characterizes the interictal EEG features associated with PPP3CA mutations: fronto-temporal interictal epileptiform discharges, hypsarrhythmia, frontal high amplitude delta activity, discontinuous activity in sleep. • PPP3CA-related DEE highlights the intricate interplay between intracellular calcium concentration, Ca2+ dependent signal transduction and epileptogenesis. The objective of this study is to characterize the electro-clinical phenotype of individuals affected by the rare PPP3CA gene-related developmental and epileptic encephalopathy (DEE). We provide a detailed electro-clinical description of four previously unreported subjects, with unremarkable structural brain MRI and a normal screening for inborn errors of metabolism, who carry pathogenic variants within the regulatory domain of the PPP3CA gene, which encodes for calcineurin. We also conducted a literature review via PubMed and SCOPUS (up to December 2023) to collect all the studies reporting clinical details of subjects with PPP3CA pathogenic variants within the regulatory domain. Our in-depth investigation reveals two distinct electro-clinical phenotypes with unique interictal and ictal patterns. Pathogenic variants within the calmodulin-binding domain result in childhood-onset epilepsy with focal and generalized seizures, developmental and intellectual impairments. Pathogenic variants within the regulatory domain lead to early onset drug-resistant severe epilepsy and potentially fatal outcomes. Comparative analysis with existing literature corroborates the notion that truncating mutations, prevalent in the regulatory domain but also possible in the calmodulin-binding domain, consistently associate with more profound disabilities and drug-resistant epilepsy. Our study emphasizes the critical role of pathogenic variants' type and location on the severity of PPP3CA-related DEE. We also speculate, based on peculiar EEG patterns, on potential pathophysiological mechanisms involving calcineurin dysfunction and calcium homeostasis. In order to improve our understanding of this rare DEE, we need both collaborative efforts to gather larger cohorts and further experimental studies. [ABSTRACT FROM AUTHOR]

Objective: To develop a high‐throughput sequencing panel for the diagnosis of developmental and epileptic encephalopathy in Tunisia and to clarify the frequency of disease‐causing genes in this region. Methods: We developed a custom panel for next‐generation sequencing of the coding sequences of 116 genes in individuals with developmental and epileptic encephalopathy from the Tunisian population. Segregation analyses and in silico studies have been conducted to assess the identified variants' pathogenicity. Results: We report 12 pathogenic variants in SCN1A, CHD2, CDKL5, SZT2, KCNT1, GNAO1, PCDH19, MECP2, GRIN2A, and SYNGAP1 in patients with developmental and epileptic encephalopathy. Five of these variants are novel: "c.149delA, p.(Asn50MetfsTer26)" in CDKL5; "c.3616C > T, p.(Arg1206Ter)" in SZT2; "c.111_113del, p.(Leu39del)" in GNAO1; "c.1435G>C, p.(Asp479His)" in PCDH19; and "c.2143delC, p.(Arg716GlyfsTer10)" in SYNGAP1. Additionally, for four of our patients, the genetic result facilitated the choice of the appropriate treatment. Significance: This is the first report of a custom gene panel to identify genetic variants implicated in developmental and epileptic encephalopathy in the Tunisian population as well as the North African region (Tunisia, Egypt, Libya, Algeria, Morocco) with a diagnostic rate of 30%. This high‐throughput sequencing panel has considerably improved the rate of positive diagnosis of developmental and epileptic encephalopathy in the Tunisian population, which was less than 15% using Sanger sequencing. The benefit of genetic testing in these patients was approved by both physicians and parents. [ABSTRACT FROM AUTHOR]

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Although there are numerous treatment options already available for epilepsy, over 30% of patients remain resistant to these antiseizure medications (ASMs). Historically, ASM discovery has relied on the demonstration of efficacy through the use of 'traditional' acute invivo seizure models (e.g. maximal electroshock, subcutaneous pentylenetetrazol, and kindling). However, advances in genetic sequencing technologies and remaining medical needs for people with treatment-resistant epilepsy or special patient populations have encouraged recent efforts to identify novel compounds in syndrome-specific models of epilepsy. Syndrome-specific models, including Scn1a variant models of Dravet syndrome and APP/PS1 mice associated with familial early-onset Alzheimer's disease, have already led to the discovery of two mechanistically novel treatments for developmental and epileptic encephalopathies (DEEs), namely cannabidiol and soticlestat, respectively. Areas covered: In this review, the authors discuss how it is likely that next-generation drug discovery efforts for epilepsy will more comprehensively integrate syndrome-specific epilepsy models into early drug discovery providing the reader with their expert perspectives. Expert opinion: The percentage of patients with pharmacoresistant epilepsy has remained unchanged despite over 30 marketed ASMs. Consequently, there is a high unmet need to reinvent and revise discovery strategies to more effectively address the remaining needs of patients with specific epilepsy syndromes, including drug-resistant epilepsy and DEEs. [ABSTRACT FROM AUTHOR]

Background: Developmental and Epileptic Encephalopathies (DEEs) are defined by drug-resistant seizures and neurodevelopmental disorders. Over 50% of patients have a genetic cause. Studies have shown that patients with DEEs, regardless of genetic diagnosis, experience a central visual function disorder known as Cerebral (cortical) Visual Impairment (CVI). The prevalence of CVI in DEE patients is currently unknown. A quantitative synthesis of existing data on the prevalence rates of this condition would aid in understanding the magnitude of the problem, outlining future research, and suggesting the need for therapeutic strategies for early identification and prevention of the disorder. Methods: The protocol followed the PRISMA-P statement for systematic review and meta-analysis protocols. The review will adhere to the JBI Manual for Evidence Synthesis (Systematic Reviews of Prevalence and Incidence) and use the CoCoPop framework to establish eligibility criteria. We will conduct a comprehensive search of several databases, including MEDLINE, EMBASE, Science Direct, Scopus, PsychINFO, Wiley, Highwire Press, and Cochrane Library of Systematic Reviews. Our primary focus will be determining the prevalence of cerebral visual impairments (Condition) in patients with developmental and epileptic encephalopathy (Population). To ensure clarity, we will provide a narrative summary of the risk of bias in the studies we include. The Cochrane Q statistic will be used to assess heterogeneity between studies. If the quantitative synthesis includes more than 10 studies, potential sources of heterogeneity will be investigated through subgroup and meta-regression analyses. Meta(bias)es analysis will also be performed. The quality of evidence for all outcomes will be evaluated using the Grading of Recommendations Assessment Development and Evaluation (GRADE) working group methodology. Discussion: This protocol outlines a systematic review and meta-analysis to identify, collect, evaluate, and integrate epidemiological knowledge related to the prevalence of CVI in patients with DEEs. To the best of our knowledge, no other systematic review and meta-analysis has addressed this specific issue. The results will provide useful information for understanding the extent of the problem, outlining future research, and suggesting the need for early identification strategies. Systematic review registrations: This Systematic Review Protocol was registered in PROSPERO (CRD42023448910). [ABSTRACT FROM AUTHOR]

Background: The ryanodine receptor 3 (RYR3) is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum and subsequent T-tubule depolarization. It is also expressed in the brain, and variants in the RYR3 gene can lead to congenital myopathy type 20 (MIM: #620310). Methods: We retrospectively analyzed the clinical characteristics and prognosis of a case of West syndrome, developmental and epileptic encephalopathy (DEE) caused by a missense variant in the RYR3 gene. We also reviewed and summarized the literature on epilepsy cases caused by RYR3 gene variants. Results: A 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. Treatment with various antiepileptic drugs resulted in initial improvement but ultimately failed to control the seizures. Whole-exome sequencing revealed a novel heterozygous variant c.10943C  >  T/p.T3648M in the RYR3 gene, and genome-wide sequencing ruled out other potentially pathogenic variants. Three previous reports have described RYR3 variants causing DEE, two of which were attributed to de novo heterozygous variants, and one was a compound heterozygote. Conclusion: The present case of DEE caused by a RYR3 heterozygous variant is consistent with previous rare cases of epilepsy caused by RYR3 gene variants in terms of pathogenesis and clinical features, but significantly different from congenital myopathy type 20. Our findings provide important evidence for the diagnosis of RYR3-related DEE, and we hypothesize that RYR3 gain-of-function variants resulting in “leaky” Ca2+ release channels may be a molecular genetic feature leading to DEE rather than myopathy. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathy 93 (DEE93) is a new defined autosomal dominant neurologic disorder caused by heterozygous mutations in the ATP6V1A gene on chromosome 3q13. DEE93 is characterized by developmental delay, early‐onset refractory seizures, hypotonia, and intellectual disability. So far, merely 31 cases caused by ATP6V1A gene mutation have been reported in literature worldwide, and early genetic detection is required for differential diagnosis. Here, we analyze the clinical and genetic features of two patients with two novel ATP6V1A mutations (c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu)) and expound the therapeutic schedule for epilepsy. We also review the reported mutations and genotypes associated with the disorder. Our study expands the clinical and genetic spectrum of ATP6V1A mutation‐associated DEE93, which provides a basis for the diagnosis, treatment, and genetic counseling of the disorder. [ABSTRACT FROM AUTHOR]

SCN2A -related disorders secondary to altered function in the voltage-gated sodium channel Nav1.2 are rare, with clinically heterogeneous expressions that include epilepsy, autism and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relationship to channel function, 81 patients (36 female, 44%, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their Nav1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal onset, n = 27; infant onset, n = 18; and later onset n = 24; and autism without seizures, n = 12) was strongly correlated with a non-seizure severity index (P = 0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (P = 0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland Adaptive Behavior composite score of 49.5 (>3 standard deviations below the norm-referenced mean of the test). Epileptic spasms were significantly more common in infant-onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (P = 0.007). Primary phenotype was also strongly correlated with variant function (P < 0.0001); gain-of-function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy and to severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups, representing: (i) primarily later-onset epilepsy with moderate loss-of-function variants and low severity indices; (ii) mostly infant-onset epilepsy with moderate loss-of-function variants but higher severity indices; and (iii) late-onset and autism only, with the lowest severity indices (mostly zero) and severe/complete loss-of-function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relationship between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on Nav1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A -related disorders advance towards clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: We aimed to develop consensus for diagnosis/management of SCN8A‐related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A‐related disorders. Methods: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty‐eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%–79% fully/partially agree, <10% disagree. Results: Early diagnosis is important for long‐term clinical outcomes in SCN8A‐related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self‐limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first‐line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first‐line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First‐line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. Significance: This is the first‐ever global consensus for the diagnosis and treatment of SCN8A‐related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence‐based care and empowers SCN8A families to advocate for their children. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A‐related disorders. Methods: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified‐Delphi process. Twenty‐eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified‐Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%–79% fully or partially agree, <10% disagree. Results: Consensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non‐seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep‐related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE. Significance: Significant comorbidities are present in most phenotypes of SCN8A‐related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long‐term management for patients with these comorbidities and provide the basis for future evidence‐based studies on optimal treatments of SCN8A‐related disorders. Identifying the prognosis of patients with SCN8A‐related disorders will also improve care and quality‐of‐life for patients and their caregivers. [ABSTRACT FROM AUTHOR]

Objective: KCNT1‐related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep‐related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug‐resistant seizures and global developmental delays. In addition to conventional anti‐seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD—including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients. Methods: We performed a literature review on PubMed and EMBase with the keyword "KCNT1" and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype. Results: A total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%–25% of patients). Significance: Ketogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug‐resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1‐related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors. Plain Language Summary: We performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti‐seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion. [ABSTRACT FROM AUTHOR]

RHOBTB2 is a member of the Rho GTPases subfamily of signaling proteins, known tumor suppressors whose loss of function and decreased expression is associated with cancer onset. Beyond its cancer-related role, RHOBTB2 is implicated in rare neurodevelopmental disorders, specifically RHOBTB2-related disorders, recognized in 2018 as a subtype of developmental and epileptic encephalopathies (DEE). Common symptoms of these disorders include early-onset epilepsy, severe intellectual disability, microcephaly, and movement disorders. Few studies have investigated patient variants associated with RHOBTB2-related disorders, and the impact of these variants on protein function remains unclear. Limited research suggests that the accumulation of RHOBTB2 in neural tissues contributes to the development of DEE. Similarly, preclinical studies indicate that missense variants near or in the BTB domain of RHOBTB2 result in decreased degradation of RHOBTB2 and the onset of DEE, whereas variants in the GTPase domain cause more variable neurodevelopmental symptoms, but do not impair proteasomal degradation of RHOBTB2. However, the exact pathophysiological mechanisms are unclear and may differ across variants. Current treatment approaches for individuals with RHOBTB2-related DEE involve the use of antiseizure medications to decrease seizures; however, no treatments have been identified that address the other symptoms or the underlying pathophysiological mechanisms associated with these disorders. Overall, RHOBTB2 remains an understudied protein with limited information on its function and how it contributes to disease mechanisms. This review provides an overview of the current knowledge of RHOBTB2 function, with an emphasis on its association with neurodevelopmental disorders through an analysis of preclinical studies and case reports that link individual variants with clinical features.

Abstract GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient’s iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy.

Abstract Objective Mutations in the cyclin‐dependent kinase‐like 5 gene (CDKL5) are associated with a wide spectrum of clinical presentations. Early‐onset epileptic encephalopathy (EOEE) is the most recognized phenotype. Here we describe phenotypic features in eight Tunisian patients with CDKL5‐related encephalopathy. Methods We included all cases with clinical features consistent with CDKL5‐related encephalopathy: infantile epileptic spasm, acquired microcephaly, movement disorders and visual impairment. We collected data about seizure types, electroencephalogram, magnetic resonance imaging, and metabolic analysis. The diagnosis of CDKL5 mutation was made thanks to Sanger sequencing with an ABI PRISM 3100‐Avant automated DNA sequencer using a Big Dye Terminator Cycle Sequencing Reaction Kit v1.1. and Next Generation Sequencing (NGS) since the development of a gene panel responsible for DEE within the framework of “Strengthening the Sfax University Expertise for diagnosis and management of epileptic encephalopathies”. Results We collected four boys and four girls aged meanly 6 years old with confirmed mutation on CDKL5 gene. Overall, we identified five de novo CDKL5 mutations including three Frame‐shift mutations, one missense mutation, and a splicing variant. The mean age at first seizure onset was 4 months. The first seizure type was infantile epileptic spasm (4/8) followed by tonic (2/8) and myoclonic seizures (2/8). Out of eight cases, four exhibited two stages epileptic course while epilepsy in three other patients progressed on three stages. Regarding development, most cases (6/8) had psychomotor retardation from the start whilst the two others showed psychomotor regression with the onset of seizures. Additional clinical features included visual impairment (7/8), tone abnormalities (7/8), stereotypies (7/8), and acquired microcephaly (6/8). Significance Our present report delineates an unusual phenotype of CDKL5‐related encephalopathy with male gender predominance and delayed onset epilepsy. It interestingly described new phenotypic features and uncommon benign developmental profiles in boys, different patterns of CDKL5‐epilepsy, neuroimaging findings, and CDKL5 mutational spectrum.

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

GNAO1 encodes G protein subunit alpha O1 (Gαo). Pathogenic variations in GNAO1 cause developmental delay, intractable seizures, and progressive involuntary movements from early infancy. Because the functional role of GNAO1 in the developing brain remains unclear, therapeutic strategies are still unestablished for patients presenting with GNAO1-associated encephalopathy. We herein report that siRNA-mediated depletion of Gnao1 perturbs the expression of transcripts associated with Rho GTPase signaling in Neuro2a cells. Consistently, siRNA treatment hampered neurite outgrowth and extension. Growth cone formation was markedly disrupted in monolayer neurons differentiated from iPSCs from a patient with a pathogenic variant of Gαo (p.G203R). This variant disabled neuro-spherical assembly, acquisition of the organized structure, and polarized signals of phospho-MLC2 in cortical organoids from the patient’s iPSCs. We confirmed that the Rho kinase inhibitor Y27632 restored these morphological phenotypes. Thus, Gαo determines the self-organizing process of the developing brain by regulating the Rho-associated pathway. These data suggest that Rho GTPase pathway might be an alternative target of therapy for patients with GNAO1-associated encephalopathy. [ABSTRACT FROM AUTHOR]

Developmental and Epileptic Encephalopathies (DEE) are a genetically diverse group of severe, early onset seizure disorders. DEE are normally identified clinically in the first six months of life by the presence of frequent, difficult to control seizures and accompanying stalling or regression of development. DEE75 results from de novo mutations of the NEUROD2 gene that result in loss of activity of the encoded transcription factor, and the seizure phenotype was shown to be recapitulated in Xenopus tropicalis tadpoles. We used CRISPR/Cas9 to make a DEE75 model in Xenopus laevis , to further investigate the developmental etiology. NeuroD2.S CRISPR/Cas9 edited tadpoles were more active, swam faster on average, and had more seizures (C-shaped contractions resembling unprovoked C-start escape responses) than their sibling controls. Live imaging of Ca2+ signaling revealed prolongued, strong signals sweeping through the brain, indicative of neuronal hyperactivity. While the resulting tadpole brain appeared grossly normal, the blood-brain barrier (BBB) was found to be leakier than that of controls. Additionally, the TGFβ antagonist Losartan was shown to have a short-term protective effect, reducing neuronal hyperactivity and reducing permeability of the BBB. Treatment of NeuroD2 CRISPant tadpoles with 5 mM Losartan decreased seizure events by more than 4-fold compared to the baseline. Our results support a model of DEE75 resulting from reduced NeuroD2 activity during vertebrate brain development, and indicate that a leaky BBB contributes to epileptogenesis. [ABSTRACT FROM AUTHOR]

Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease. This paper establishes missense variants in the anoctamin family member ANO4 (or TMEM16D) as a cause of distinct epileptic disorders. Resulting phenotypes depend on the location in the protein and the functional impact of the substitution such as loss of cation channel function and increased apoptosis signaling. [ABSTRACT FROM AUTHOR]

ARV1 mutation is known to present as developmental and epileptic encephalopathy (DEE)-38. However, the phenotypic spectrum has been expanding ever since it was reported in 2016. Along with seizures and developmental delay, other unique clinical features include ophthalmological abnormalities and movement disorders in the form of ataxia and dystonia, especially in those with missense mutation. These manifestations closely mimic ataxia telangiectasia. Elevation of alpha-fetoprotein levels is an important investigative marker in the diagnosis of ataxia telangiectasia and ataxia with oculomotor apraxia syndromes. ARV1 can also be associated with increased alpha-fetoprotein. There are no reports evaluating alpha-fetoprotein levels in cases with ARV1 mutation, which is significant in the context of ocular abnormalities with ataxia. We report a case of ARV1 mutation presenting with ataxia, ocular abnormalities, and elevated alpha-fetoprotein levels, thus mimicking autosomal recessive cerebellar ataxias. This study provides a comprehensive literature review of the cases reported so far, thus expanding the understanding of the spectrum of presentation, and helps in correlating the clinical picture with the underlying causative genetic mutation. ARV1 gene is another example of one gene with phenotypic pleiotropy. Though presentation with DEE is common, a few, especially those with missense mutations, can present with ataxia and ocular abnormalities. All cases presenting with ataxia who have increased alpha-fetoprotein levels and seizures should be tested for the ARV1 gene, when testing for ataxia genes is negative. The underlying genetic mechanism can explain the varying clinical manifestations of the ARV1 gene. [ABSTRACT FROM AUTHOR]

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

Objective: Mutations in the cyclin‐dependent kinase‐like 5 gene (CDKL5) are associated with a wide spectrum of clinical presentations. Early‐onset epileptic encephalopathy (EOEE) is the most recognized phenotype. Here we describe phenotypic features in eight Tunisian patients with CDKL5‐related encephalopathy. Methods: We included all cases with clinical features consistent with CDKL5‐related encephalopathy: infantile epileptic spasm, acquired microcephaly, movement disorders and visual impairment. We collected data about seizure types, electroencephalogram, magnetic resonance imaging, and metabolic analysis. The diagnosis of CDKL5 mutation was made thanks to Sanger sequencing with an ABI PRISM 3100‐Avant automated DNA sequencer using a Big Dye Terminator Cycle Sequencing Reaction Kit v1.1. and Next Generation Sequencing (NGS) since the development of a gene panel responsible for DEE within the framework of "Strengthening the Sfax University Expertise for diagnosis and management of epileptic encephalopathies". Results: We collected four boys and four girls aged meanly 6 years old with confirmed mutation on CDKL5 gene. Overall, we identified five de novo CDKL5 mutations including three Frame‐shift mutations, one missense mutation, and a splicing variant. The mean age at first seizure onset was 4 months. The first seizure type was infantile epileptic spasm (4/8) followed by tonic (2/8) and myoclonic seizures (2/8). Out of eight cases, four exhibited two stages epileptic course while epilepsy in three other patients progressed on three stages. Regarding development, most cases (6/8) had psychomotor retardation from the start whilst the two others showed psychomotor regression with the onset of seizures. Additional clinical features included visual impairment (7/8), tone abnormalities (7/8), stereotypies (7/8), and acquired microcephaly (6/8). Significance: Our present report delineates an unusual phenotype of CDKL5‐related encephalopathy with male gender predominance and delayed onset epilepsy. It interestingly described new phenotypic features and uncommon benign developmental profiles in boys, different patterns of CDKL5‐epilepsy, neuroimaging findings, and CDKL5 mutational spectrum. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early‐onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10‐year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic–clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype–genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients. [ABSTRACT FROM AUTHOR]

CLCN4-related disorder is a rare X-linked neurodevelopmental condition with a pathogenic mechanism yet to be elucidated. CLCN4 encodes the vesicular 2Cl−/H+ exchanger ClC-4, and CLCN4 pathogenic variants frequently result in altered ClC-4 transport activity. The precise cellular and molecular function of ClC-4 remains unknown; however, together with ClC-3, ClC-4 is thought to have a role in the ion homeostasis of endosomes and intracellular trafficking. We reviewed our research database for patients with CLCN4 variants and epilepsy, and performed thorough phenotyping. We examined the functional properties of the variants in mammalian cells using patch-clamp electrophysiology, protein biochemistry, and confocal fluorescence microscopy. Three male patients with developmental and epileptic encephalopathy were identified, with differing phenotypes. Patients #1 and #2 had normal growth parameters and normal-appearing brains on MRI, while patient #3 had microcephaly, microsomia, complete agenesis of the corpus callosum and cerebellar and brainstem hypoplasia. The p.(Gly342Arg) variant of patient #1 significantly impaired ClC-4's heterodimerization capability with ClC-3 and suppressed anion currents. The p.(Ile549Leu) variant of patient #2 and p.(Asp89Asn) variant of patient #3 both shift the voltage dependency of transport activation by 20 mV to more hyperpolarizing potentials, relative to the wild-type, with p.(Asp89Asn) favouring higher transport activity. We concluded that p.(Gly342Arg) carried by patient #1 and the p.(Ile549Leu) expressed by patient #2 impair ClC-4 transport function, while the p.(Asp89Asn) variant results in a gain-of-transport function; all three variants result in epilepsy and global developmental impairment, but with differences in epilepsy presentation, growth parameters, and presence or absence of brain malformations. [ABSTRACT FROM AUTHOR]

GRIN -related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2–18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B , GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5–28, prevalence = 5.8–60.8; DS: incidence proportion = 2.2–6.5, prevalence = 1.2–6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6–9.2 years; LGS, 2–15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person‐years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria. [ABSTRACT FROM AUTHOR]

Objective: To delineate the comprehensive phenotypic spectrum of SYNGAP1‐related disorder in a large patient cohort aggregated through a digital registry. Methods: We obtained de‐identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1. We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein. Results: We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy. Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p =.014) and sleep problems (OR 2.41, p =.015) but not necessarily those with autistic traits. Patients with variants in exons 1–4 were more likely to have the ability to speak in phrases vs those with variants in exons 5–19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif. Significance: We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1‐related disorder and add additional genotype–phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases. [ABSTRACT FROM AUTHOR]

WWOX developmental and epileptic encephalopathy is characterised by drug-resistant epilepsy with onset within the first year of life and severe psychomotor developmental delay. This report presents for the first time a clinical case of an adult patient with a homozygous likely pathogenic variant (p.Thr12Met) in the WWOX gene, with more than 40 years of follow-up. The patient had refractory epilepsy with various types of seizures during his life: mainly epileptic spasms, autonomic, myoclonic, tonic seizures, and absences. The patient had a prominent developmental delay with a lack of expressive speech, but by the age of 3, he had acquired the skills to sit, crawl, and walk with support. In adolescence, there was an acute regression of acquired skills to a total absence of independent motor activity. The patient had dysmorphic features, such as upslanting palpebral fissures, arched eyebrows, and hypertelorism. For many years, the patient was given a diagnosis of cerebral palsy; 38 years after the onset of the disease, he was given a molecular genetic diagnosis of WWOX-associated developmental and epileptic encephalopathy. Our observation illustrates the natural history of WWOX-DEE and the high clinical significance of early genetic diagnostics for identifying the cause of developmental delay and resistant epilepsy.

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