Efficacy and safety of stiripentol in the prevention and cessation of status epilepticus: A systematic review.

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.

Early mortality in STXBP1-related disorders.

INTRODUCTION: Pathogenic variants in STXBP1 cause a spectrum of disorders mainly consisting of developmental and epileptic encephalopathy (DEE), often featuring drug-resistant epilepsy. An increased mortality risk occurs in individuals with drug-resistant epilepsy and DEE, with sudden unexpected death in epilepsy (SUDEP) often the major cause of death. This study aimed to identify the rate and causes of mortality in STXBP1-related disorders. METHODS: Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease. RESULTS: We estimated a mortality rate of 3.2% (31/966), based on the STXBP1 Foundation and the STXBP1 Global Connect registry. In total, we analyzed data on 40 individuals (23 males) harboring pathogenic STXBP1 variants, collected from different centers worldwide. They died at a median age of 13 years (range: 11 months-46 years). The most common cause of death was SUDEP (36%), followed by pulmonary infections and respiratory complications (33%). The incidence of SUDEP peaked in mid-childhood, while non-SUDEP causes were more frequent in early childhood or adulthood (p = 0.006). In the most severe phenotypes, death was related to non-SUDEP causes (p = 0.018). CONCLUSION: We found a mortality rate in STXBP1-related disorders similar to other DEEs, with an early age at death and SUDEP as well as pulmonary infections as the main cause of death. These findings assist in prognostic evaluation and genetic counseling for the families. They help to define the mortality risk of STXBP1-related disorders and implement preventative strategies.

A roadmap to cure CHD2-related disorders.

Coalition to Cure CHD2 (CCC) is a patient advocacy group dedicated to improving the lives of those affected by CHD2-related disorders (CHD2-RD) by increasing education, building community, and accelerating research to uncover a cure. CHD2 is a chromatin remodeler that was identified in 2013 as being a genetic cause for developmental and epileptic encephalopathies. Pathogenic changes in CHD2 can cause treatment-resistant epilepsy, intellectual and developmental delays, and autism, and some individuals experience neurodevelopmental regression. There are currently no targeted therapies available for CHD2-related disorders. Haploinsufficiency of CHD2 is a causative mechanism of disease for individuals with pathogenic variants (primarily truncating) in CHD2. Recently, identification of individuals with deletion of nearby gene CHASERR, a regulator of CHD2 gene expression, has established dosage sensitivity in CHD2 and solidified the CHASERR gene as a potential therapeutic target for CHD2 levels. Through collaboration with our community and our scientific advisory board, CCC has created a Roadmap to Cure CHD2 as our guide toward a targeted cure that can benefit our community, with steps including (1) identifying and defining patients, (2) developing models of CHD2, (3) studying models of CHD2, (4) testing therapies, (5) involving patients, and (6) reaching a cure. Despite some of the challenges inherent in CHD2 research including establishing animal and cellular models that recapitulate the CHD2 clinical phenotype, identifying measurable outcomes and reliable biomarkers, or testing emerging therapeutic approaches, CCC continues to engage with our community to support ongoing research that aligns with our priorities. CCC sees new and exciting opportunities for additional research that can move our community toward our common goal of a cure that will improve the lives of individuals and their families now and in the future.

A roadmap to cure disorders caused by the CHD2 and CHASERR genes Coalition to Cure CHD2 (CCC) is a nonprofit founded in October 2020 to fund research towards a cure for individuals with CHD2-related disorders. The CHD2 gene was discovered as a genetic cause for epilepsy in 2013. Individuals with CHD2 typically experience seizures that can be resistant to treatment, intellectual disability, delayed development, autism, and other symptoms. The nearby CHASERR gene has been found to regulate CHD2 and is a possible therapeutic target. Individuals with a deletion of CHASERR have been identified - these individuals have too much CHD2 and more severe symptoms. CCC has created a Roadmap to Cure CHD2 as a guide for their journey towards a targeted cure for CHD2-related disorders. The steps in the roadmap include: (1) identify and define patients, (2) develop models of CHD2, (3) study models of CHD2, (4) test therapies, (5) involve patients, (6) reach a cure. CCC has worked with CHD2 families to identify family-level priorities for therapeutic development (e.g. seizures, behavior, etc), to capture the impact of disease through qualitative research, and to collect patient health data and tissue samples for scientific analysis. The development of CHD2 models, mouse models in particular, has been challenging as the mice do not develop seizures. Additional models are underway including frogs, zebrafish, and patient-derived cells. These models have provided crucial insight into the biology of CHD2 but scientific questions remain unanswered. A variety of therapeutic approaches have been proposed including novel treatments that directly target CHD2 biology as well as the repurposing of existing FDA-approved compounds. Establishing measurable outcomes, including biomarkers, and finding treatments that can reach the brain will be important. By continuing to follow this roadmap, the CCC believes that one day there will be a cure for CHD2-related disorders.

[Neonatal epileptics syndromes]. / Síndromes epilépticos neonatales.

Neonatal epileptic syndromes are part of the genetic and metabolic epilepsies in this age group. Although they are not the most frequent cause of neonatal seizures, their early recognition allows for better diagnostic and therapeutic approaches. These syndromes can be classified into self-limited neonatal syndromes and early infantile epileptic and developmental encephalopathies (EIDEE). While they may share semiology in some types of seizures, such as sequential, and even share alterations in common genes in their etiology, their evolution is very different. In self-limited neonatal syndromes, seizures typically resolve within the first months of life with normal psychomotor development, giving rise to the term self-limited. However, the term benign should not be used as some may present recurrence of seizures, movement disorders, or learning disorders. In the case of EIDEE, seizures are usually refractory to treatment, affecting brain functions and neurodevelopment. In this review, our aim was to describe the electroclinical phenotype of neonatal epileptic syndromes, the most frequently involved genes and their clinical spectrum, their diagnostic approach, as well as the recommended treatments.

Los síndromes epilépticos neonatales hacen parte de las epilepsias de origen genético y metabólico en este grupo edad y aunque no son la causa más frecuente de crisis neonatales, su reconocimiento temprano permite dirigir mejor su enfoque diagnóstico y tratamiento. Pueden clasificarse en síndromes neonatales autolimitados y encefalopatías epilépticas y del desarrollo infantil temprano (EIDEE). Aunque pueden mostrar semiología similar en algunos tipos de crisis, como las secuenciales, e incluso comparten alteraciones en genes comunes en su etiología, su evolución es muy diferente. En los síndromes autolimitados, las crisis remiten en los primeros meses de vida alcanzando un desarrollo psicomotor normal, lo que da su nombre de autolimitado; sin embargo, el término benigno no debe utilizarse dado que algunos pueden presentar recurrencia de crisis, trastornos del movimiento o trastornos del aprendizaje. En las EIDEE las crisis suelen ser refractarias al tratamiento y se comprometen funciones cerebrales y el neurodesarrollo. En esta revisión describiremos el fenotipo electroclínico de los síndromes epilépticos neonatales, los genes más frecuentemente involucrados y su espectro clínico, su enfoque diagnóstico, así como los tratamientos recomendados.

Rest-Activity Rhythm Phenotypes in Adults with Epilepsy and Intellectual Disability.

Objective: Sleep and rest-activity rhythms (RARs) are perturbed in many forms of neuropsychiatric illness. In this study, we applied wrist actigraphy to describe the extent of RAR perturbations in adults with epilepsy and intellectual disability ("E+ID"), using a cross-sectional case-control design. We examined whether RAR phenotypes correlated with epilepsy severity, deficits in adaptive function and/or comorbid psychopathology. Methods: Primary caregivers of E+ID adults provided informed consent during routine ambulatory clinic visits and were asked to complete standardized surveys of overall epilepsy severity (GASE, Global Assessment of Severity of Epilepsy), adaptive function (ABAS-3, Adaptive Behavior Assessment System-3) and psychopathology (ABCL, Adult Behavior Checklist). Caregivers were also asked to ensure that subjects wore an Actiwatch-2 device continuously on their nondominant wrist for at least ten days. From recorded actograms, we calculated RAR amplitude, acrophase, robustness, intradaily variability (IV), interdaily stability (IS) and estimates of sleep quantity and timing. We compared these RAR metrics against those from (i) a previously published cohort of adults with epilepsy without ID (E-ID), and (ii) a cohort of age- and sex-matched intellectually able subjects measured within the Study of Latinos (SOL) Ancillary actigraphy study (SOL). Within E+ID subjects, we applied k-means analysis to divide subjects into three actigraphically distinct clusters. Results: 46 E+ID subjects (median age 26 [20-68], 47% female) provided a median recording duration of 11 days [range 6-27]. Surveys reflected low to extremely low levels of adaptive function (ABAS3 General Adaptive Composite score: median 50 [49-75]), and low/subclinical levels of psychopathology (ABCL total score: median 54.5 [25-67]). Compared with E-ID (n=57) and SOL (n=156) cohorts, E+ID subjects displayed significantly lower RAR amplitude, robustness and IS, with significantly higher IV and total daily sleep. K-means clustering of E+ID subjects recognized an intermediate cluster "B", with RAR values indistinguishable to E-ID. Cluster "A" subjects displayed pronounced hypoactivity and hypersomnia with high rates of rhythm fragmentation, while cluster "C" subjects featured hyper-robust and high amplitude RARs. All three clusters were similar in age, body mass index, antiseizure medication (ASM) polytherapy, ABAS3 and ABCL scores. We qualitatively describe RAR examples from all three clusters. Interpretation: We show that adults with epilepsy and intellectual disability display a wide spectrum of RAR phenotypes that do not neatly correlate with measures of adaptive function or epilepsy severity. Prospective studies are necessary to determine whether continuous actigraphic monitoring can sensitively capture changes in chronobiological health that may arise with disease progression, iatrogenesis (e.g., ASM toxicity) or acute health deteriorations (e.g., seizure exacerbation, pneumonia). Similar long-term data is necessary to recognize whether behavioral interventions targeted to 'normalize' RARs may promote improvements in adaptive function and therapy engagement.

Bipolar Disorder in a female with CDKL5 Deficiency Disorder: A Case Report.

Background: CDKL5 deficiency disorder (CDD) is an early-onset developmental and epileptic encephalopathy. While a subset of individuals is believed to experience comorbid behavioral disorders, none have reported well-defined affective disorders. Though there is a documented association between epilepsy and mood disorders, they may go undetected in the CDD population due to difficulty assessing mood in the presence of severe/profound intellectual disability and disease-related sleep dysregulation. We aimed to identify the clinical characteristics of an individual with CDD who presented with a mood disorder falling outside this expected behavioral phenotype. Case Presentation: We identified one 22-year-old female with CDD diagnosed with unspecified bipolar disorder at 18 years of age. Family history was noncontributory. At diagnosis, she had fluctuations in mood, characterized by periods of elated affect, increased energy and vocalizations, hypertonia, and insomnia lasting 3-4 days alternating with periods of depressed affect, irritability, hypotonia, and excessive sleep lasting for up to one month. She had experienced frequent mood swings and sleep dysregulation from early childhood, and by early adulthood the duration of "up" and "down" periods fell in the range specified in the DSM-5 bipolar disorder criteria. Trazodone and suvorexant did not alleviate sleep related symptoms. Her epilepsy was well controlled on lamotrigine monotherapy since early childhood. Though lamotrigine treatment has had no psychiatric benefit despite its known mood stabilizing properties, aripiprazole has been effective in reducing severity and frequency of fluctuations between hypomania and depression. Conclusions: While sleep and behavioral disorders fall within the expected phenotype for CDD, this is the first report of bipolar disorder. Careful attention to patterns of sleep and behavior that may indicate mood cycling in this population is required, particularly in the setting of limited communication and functional abilities.

PPP3CA gene-related developmental and epileptic encephalopathy: Expanding the electro-clinical phenotype.

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

New evidence supports RYR3 as a candidate gene for developmental and epileptic encephalopathy.

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.

Prevalence of cerebral visual impairment in developmental and Epileptic Encephalopathies: a systematic review protocol.

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).

Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder.

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.

Effective knockdown-replace gene therapy in a novel mouse model of DNM1 developmental and epileptic encephalopathy.

Effective gene therapy for gain-of-function or dominant-negative disease mutations may require eliminating expression of the mutant copy together with wild-type replacement. We evaluated such a knockdown-replace strategy in a mouse model of DNM1 disease, a debilitating and intractable neurodevelopmental epilepsy. To challenge the approach robustly, we expressed a patient-based variant in GABAergic neurons-which resulted in growth delay and lethal seizures evident by postnatal week three-and delivered to newborn pups an AAV9-based vector encoding a ubiquitously expressed, Dnm1-specific interfering RNA (RNAi) bivalently in tail-to-tail configuration with a neuron-specific, RNAi-resistant, codon-optimized Dnm1 cDNA. Pups receiving RNAi or cDNA alone fared no better than untreated pups, whereas the vast majority of mutants receiving modest doses survived with almost full growth recovery. Synaptic recordings of cortical neurons derived from treated pups revealed that significant alterations in transmission from inhibitory to excitatory neurons were rectified by bivalent vector application. To examine the mutant transcriptome and impact of treatment, we used RNA sequencing and functional annotation clustering. Mutants displayed abnormal expression of more than 1,000 genes in highly significant and relevant functional clusters, clusters that were abrogated by treatment. Together these results suggest knockdown-replace as a potentially effective strategy for treating DNM1 and related genetic neurodevelopmental disease.

Unraveling neuroimaging insights in developmental epileptic encephalopathy type 25: a comprehensive review of reported cases and a novel SLC13A5 variant.

Developmental and epileptic encephalopathy type 25 with amelogenesis imperfecta (DEE25) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous disease-causing variants in the SLC13A5. These variants can disrupt energy production and delay brain development, leading to DEE25. Key symptoms include refractory seizures, often manifesting in neonates or infants, alongside global developmental delay, intellectual disability, progressive microcephaly, ataxia, spasticity, and speech difficulties. Dental anomalies related to amelogenesis imperfecta are common. Previous studies have typically reported normal or minimally altered early-life brain magnetic resonance imaging (MRI) findings in DEE25. However, our investigation identified a homozygous splice donor variant (NM_177550.5: c.1437 + 1G >T) in SLC13A5 through whole-exome sequencing in two affected siblings (P1 and P2). They displayed developmental delay, cerebral hypotonia, speech delay, recurrent seizures, mild but constant microcephaly, and motor impairments. Significantly, P1 exhibited novel findings on brain magnetic resonance imaging at age 5, including previously unreported extensive persistent hypomyelination. Meanwhile, P2 showed substantial loss of cerebral white matter in the frontoparietal region and delayed myelination at 18 months old. These discoveries broaden the DEE25 imaging spectrum and highlight the clinical heterogeneity even within siblings sharing the same variants.

Epilepsies.

Recent advances in genetic diagnosis have revealed the underlying etiology of many epilepsies and have identified pathogenic, causative variants in numerous ion and ligand-gated channel genes. This chapter describes the clinical presentations of epilepsy associated with different channelopathies including classic electroclinical syndromes and emerging gene-specific phenotypes. Also discussed are the archetypal epilepsy channelopathy, SCN1A-Dravet syndrome, considering the expanding phenotype. Clinical presentations where a channelopathy is suspected, such as sleep-related hypermotor epilepsy and epilepsy in association with movement disorders, are reviewed. Channelopathies pose an intriguing problem for the development of gene therapies. Design of targeted therapies requires physiologic insights into the often multifaceted impact of a pathogenic variant, coupled with an understanding of the phenotypic spectrum of a gene. As gene-specific novel therapies come online for the channelopathies, it is essential that clinicians are able to recognize epilepsy phenotypes likely to be due to channelopathy and institute early genetic testing in both children and adults. These findings are likely to have immediate management implications and to inform prognostic and reproductive counseling.

Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.

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.

Innovative drug discovery strategies in epilepsy: integrating next-generation syndrome-specific mouse models to address pharmacoresistance and epileptogenesis.

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 in vivo 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.

Efficacy of enteral feeding by gastrostomy tube placement in patients with Lennox-Gastaut syndrome on body weight and days of hospitalization: A retrospective case series.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a severe form of drug-resistant epilepsy that begins during childhood and frequently leads to significant neurological impairments. Patients with LGS are likely to receive improper oral nutrition because of issues such as dysphagia and aspiration risk, potentially resulting in long-term tube feeding and eventual gastrostomy tube placement. Therefore, we investigated the effects of gastrostomy tube placement on nutrition outcomes and frequency of hospitalization in LGS. METHODS: We retrospectively examined 67 patients diagnosed with LGS who had undergone gastrostomy tube placement between January 2005 and August 2022. Comprehensive clinical data and complications arising from the procedure were collected. Patients' nutrition condition and frequency of hospitalizations were analyzed before and after gastrostomy tube placement. RESULTS: Gastrostomy tube placement was performed for the following reasons: high risk of aspiration (50 out of 67, 74.6%), dysphagia (13 out of 67, 25.4%), persistent nasogastric tube feeding (2 out of 67, 3.0%), and severe malnutrition (2 out of 67, 3.0%). After the procedure, z scores for weight-for-age improved significantly, shifting from -3.35 ± 3.57 to -2.54 ± 2.70 over a 2-year interval (P < 0.001). Additionally, the total days of hospitalization and days of hospitalization due to respiratory symptoms reduced significantly from 41.94 ± 51.76 to 15.27 ± 26.68 (P < 0.001) and from 23.75 ± 36.92 to 10.52 ± 22.98 (P = 0.009), respectively. Among the patients, 50 (74.6%) experienced complications resulting from gastrostomy, with a relatively small proportion of major complications (11 out of 67, 16.4%) and no mortality. CONCLUSION: Gastrostomy tube placement is a relatively safe procedure with favorable effects on nutrition status and hospitalization rates in patients with LGS.

Clinical features and genetic analysis of developmental and epileptic encephalopathy caused by biallelic variants of CACNA1B.

Objective: To analyze the clinical features and genetic etiology of a patient with developmental and epileptic encephalopathy. Methods: The clinical information and peripheral blood of the patient and their family members were collected before the whole exome sequencing analysis was performed and Sanger sequencing was employed to verify the potential variant. Results: The patient presented with epilepsy and cerebral palsy with his parents, brother, and sister being all healthy. Whole exome sequencing analysis revealed that the child carried the paternal c.823del (p. R275Gfs*31) heterozygous variant and the maternal c.2456del (p.V819Gfs*190) heterozygous variant of the CACNA1B gene. Pedigree verification found that the elder brother and amniotic fluid of fetus in womb carried the paternal c.823del heterozygous variant, and the elder sister carried the maternal c.2456del heterozygous variant, which conformed to the law of autosomal recessive inheritance. Neither of these two variants has been reported in the literature and has not been included in the Genomic Mutation Frequency Database (gnomAD); according to the American Academy of Medical Genetics and Genomics Variation Grading Guidelines (ACMG), both variants are classified as pathogenic variants (PVS1+PM2-Supporting + PM3). Conclusion: This study reported the first case of a child with neurodevelopmental disorder and epilepsy caused by a new compound heterozygous variant of the CACNA1B gene in China, clarified its genetic etiology, enriched the mutation spectrum and disease spectrum of CACNA1B gene, and provided a basis for prenatal diagnosis of the family.

Gnao1 is a molecular switch that regulates the Rho signaling pathway in differentiating neurons.

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.

[Developmental and epileptic encephalopathy produced by the ATP1A2 mutation]. / Entsefalopatiya s narusheniem razvitiya i epilepsiei, vyzvannaya mutatsiei gena ATP1A2.

A case of DEE98, a rare developmental and epileptic encephalopathy related to previously reported the de novo missense mutation p.Arg908Gln in the ATP1A2 gene, is described. A girl examined first time in 11 months had microcephaly, severe mental and motor delay, strabismus, spastic paraparesis and pachypolymicrogyria on brain MRI that is atypical for DEE98. Epilepsy with polymorphic seizures started at the age of 15 months. There was a remission lasting 9 months, after which seizures renewed. DEE98 was diagnosed at the age of 2 years 9 months by exome sequencing verified by trio Sanger sequencing. Another finding from high-throughput exome sequencing were two previously undescribed heterozygous variants of uncertain pathogenicity in the SPART gene, which causes autosomal recessive spastic paraplegia type 20 (SPG20); Sanger sequencing confirmed the trans position of the variants. The common clinical sign with typical SPG20 was early spastic paraparesis with contractures; other symptoms did not coincide. Considering the phenotypic diversity of SPG20 and the possibility of a combination of two independent diseases, we performed an additional study of the pathogenicity of SPART variants at the mRNA level: pathogenicity was not confirmed, and there were no grounds to diagnose SPG20.