Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures and EEG abnormalities on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both nongenetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity. Functional studies performed in different animal models and clinical trials on patients have contributed to elucidate pathophysiological mechanisms underlying many DEEs and have explored the efficacy of different treatments. Here, we provide an extensive review of the phenotypic spectrum included in the DEEs and of the genetic determinants and pathophysiological mechanisms underlying these conditions. We also provide a brief overview of the most effective treatment now available and of the emerging therapeutic approaches.

Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are neurodevelopmental diseases characterized by refractory epilepsy, distinct electroencephalographic and neuroradiological features, and various degrees of developmental delay. Mutations in KCNQ2, KCNQ3, and, more rarely, KCNQ5 genes encoding voltage-gated potassium channel subunits variably contributing to excitability control of specific neuronal populations at distinct developmental stages have been associated to DEEs. In the present work, the clinical features of two DEE patients carrying de novo KCNQ5 variants affecting the same residue in the pore region of the Kv7.5 subunit (G347S/A) are described. The in vitro functional properties of channels incorporating these variants were investigated with electrophysiological and biochemical techniques to highlight pathophysiological disease mechanisms. Currents carried by Kv7.5 G347 S/A channels displayed: 1) large (>10 times) increases in maximal current density, 2) the occurrence of a voltage-independent component, 3) slower deactivation kinetics, and 4) hyperpolarization shift in activation. All these functional features are consistent with a gain-of-function (GoF) pathogenetic mechanism. Similar functional changes were also observed when the same variants were introduced at the corresponding position in Kv7.2 subunits. Nonstationary noise analysis revealed that GoF effects observed for both Kv7.2 and Kv7.5 variants were mainly attributable to an increase in single-channel open probability, without changes in membrane abundance or single-channel conductance. The mutation-induced increase in channel opening probability was insensitive to manipulation of membrane levels of the critical Kv7 channel regulator PIP2. These results reveal a pathophysiological mechanism for KCNQ5-related DEEs, which might be exploited to implement personalized treatments.

Natural history of rare diseases using natural language processing of narrative unstructured electronic health records: The example of Dravet syndrome.

OBJECTIVE: The increasing implementation of electronic health records allows the use of advanced text-mining methods for establishing new patient phenotypes and stratification, and for revealing outcome correlations. In this study, we aimed to explore the electronic narrative clinical reports of a cohort of patients with Dravet syndrome (DS) longitudinally followed at our center, to identify the capacity of this methodology to retrace natural history of DS during the early years. METHODS: We used a document-based clinical data warehouse employing natural language processing to recognize the phenotype concepts in the narrative medical reports. We included patients with DS who have a medical report produced before the age of 2 years and a follow-up after the age of 3 years ("DS cohort," 56 individuals). We selected two control populations, a "general control cohort" (275 individuals) and a "neurological control cohort" (281 individuals), with similar characteristics in terms of gender, number of reports, and age at last report. To find concepts specifically associated with DS, we performed a phenome-wide association study using Cox regression, comparing the reports of the three cohorts. We then performed a qualitative analysis of the surviving concepts based on their median age at first appearance. RESULTS: A total of 76 concepts were prevalent in the reports of children with DS. Concepts appearing during the first 2 years were mostly related with the epilepsy features at the onset of DS (convulsive and prolonged seizures triggered by fever, often requiring in-hospital care). Subsequently, concepts related to new types of seizures and to drug resistance appeared. A series of non-seizure-related concepts emerged after the age of 2-3 years, referring to the nonseizure comorbidities classically associated with DS. SIGNIFICANCE: The extraction of clinical terms by narrative reports of children with DS allows outlining the known natural history of this rare disease in early childhood. This original model of "longitudinal phenotyping" could be applied to other rare and very rare conditions with poor natural history description.

Predictors of drug-resistant epilepsy in childhood epilepsy syndromes: A subgroup analysis from a prospective cohort study.

OBJECTIVE: Previous studies assessing factors associated with drug-resistant epilepsy (DRE) were constrained by their amalgamation of all epilepsy syndromes in their analyses and the absence of uniform criteria for defining DRE. Our objective was to identify predictors of DRE among the four primary childhood epilepsy syndrome groups within a cohort of children with new onset seizures, using the International League Against Epilepsy (ILAE) definition of DRE and the recent classification of epilepsies. METHODS: This is a prospective study of 676 children with new onset seizures initiated on antiseizure medication. Patients were monitored for the occurrence of DRE according to the ILAE criteria and were categorized into one of four epilepsy groups: self-limited focal epilepsies (SeLFEs), genetic generalized epilepsies (GGEs), developmental epileptic encephalopathies (DEEs), and focal epilepsies. Cox regression analysis was performed to identify predictors of DRE within each epilepsy group. RESULTS: Overall, 29.3% of children were classified as having DRE, with the highest incidence observed among children diagnosed with DEEs (77.7%), followed by focal epilepsies (31.5%). Across the entire cohort, predictors of DRE included the presence of an epileptogenic lesion, a higher pretreatment number of seizures, experiencing multiple seizure types, presence and severity of intellectual and developmental delay, myoclonus, and younger age at epilepsy onset. Within the GGEs, only a younger age at seizure onset and experiencing multiple seizure types predicted DRE. Among focal epilepsies, predictors of DRE included the presence of an epileptogenic lesion, experiencing multiple seizure types, and having a greater number of pretreatment seizures. Within the DEEs, predictors of DRE were the occurrence of tonic seizures. Predictors of DRE within SeLFEs could not be identified. SIGNIFICANCE: This study indicates that different epilepsy syndromes are associated with distinct predictors of drug resistance. Anticipation of drug resistance within various groups is feasible using accessible clinical variables throughout the disease course.

Voltage-gated sodium channel epilepsies in a tertiary care center: Phenotypic spectrum with correlation to predicted functional effects.

BACKGROUND: Variants in sodium channel genes (SCN) are strongly associated with epilepsy phenotypes. Our aim in this study to evaluate the genotype and phenotype correlation of patients with SCN variants in our tertiary care center. METHODS: In this retrospective study, patients with SCN variants and epilepsy who were followed up at our clinic between 2018 and 2022 were evaluated. Our study discussed the demographics of the patients, the seizure types, the age of seizure onset, the SCN variants, the domains and the functions of the variants, the magnetic resonance imaging findings, the motor, cognitive, and psychiatric comorbidities, and the response to anti-seizure medication. Genetic testing was conducted using a next-generation sequencing gene panel (epilepsy panel) or a whole-exome sequencing. For evaluating variant function, we used a prediction tool (https://funnc.shinyapps.io/shinyappweb/ site). To assess protein domains, we used the PER viewer (http://per.broadinstitute.org/). RESULTS: Twenty-three patients with SCN variants and epilepsy have been identified. Sixteen patients had variants in the SCN1A, six patients had variants in the SCN2A, and one patient had a variant in the SCN3A. Two novel SCN1A variants and two novel SCN2A variants were identified. The analysis revealed 14/23 missense, 6/23 nonsense, 2/23 frameshift, and 1/23 splice site variants in the SCN. There are seven variants predicted to be gain-of-function and 13 predicted to be loss-of-function. Among 23 patients; 11 had Dravet Syndrome, 6 had early infantile developmental and epileptic encephalopathy, three had genetic epilepsy with febrile seizures plus spectrum disorder, one had self-limited familial neonatal-infantile epilepsy, one had self-limited infantile epilepsy and one had infantile childhood development epileptic encephalopathy. CONCLUSION: Our cohort consists of mainly SCN1 variants, most of them were predicted to be loss of function. Dravet syndrome was the most common phenotype. The prediction tool used in our study demonstrated overall compatibility with clinical findings. Due to the diverse clinical manifestations of variant functions, it may assist in guiding medication selection and predicting outcomes. We believe that such a tool will help the clinician in both prognosis prediction and solving therapeutic challenges in this group where refractory seizures are common.

X-Linked Epilepsies: A Narrative Review.

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype-phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

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

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

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

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

Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.

More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10-5) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10-6), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10-11), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.

NAPB and developmental and epileptic encephalopathy: Description of the electroclinical profile associated with a novel pathogenic variant.

Developmental and epileptic encephalopathies (DEE) are a group of neurodevelopmental disorders characterized by epileptic seizures associated with developmental delay or regression. DEE are genetically heterogeneous, and the proteins involved play roles in multiple pathways such as synaptic transmission, metabolism, neuronal development or maturation, transcriptional regulation, and intracellular trafficking. We performed whole exome sequencing on a consanguineous family with three children presenting an early onset (<6 months) with clusters of seizures characterized by oculomotor and vegetative manifestations, with an occipital origin. Before 1 year of age, interictal electroencephalographic recordings were well organized and neurodevelopment was unremarkable. Then, a severe regression occurred. We identified a novel homozygous protein-truncating variant in the NAPB (N-ethylmaleimide-sensitive fusion [NSF] attachment protein beta) gene that encodes the ßSNAP protein, a key regulator of NSF-adenosine triphosphatase. This enzyme is essential for synaptic transmission by disassembling and recycling proteins of the SNARE complex. Here, we describe the electroclinical profile of each patient during the disease course. Our findings strengthen the association between biallelic variants in NAPB and DEE and refine the associated phenotype. We suggest including this gene in the targeted epilepsy gene panels used for routine diagnosis of unexplained epilepsy.

Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. RESULTS: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. SIGNIFICANCE: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

Evaluating adult care in Dravet syndrome upon transferring from pediatrics in the U.S.: A caregiver-based survey study.

Patients with Dravet syndrome (DS) and their caregivers must navigate a complex process upon transitioning from pediatric to adult healthcare settings. Our study examines the state of care transfer of patients with DS in the U.S. A 34-question e-survey evaluating patient demographics, clinical features, and details of the transfer process was sent to caregivers of adults with DS (≥18 years old) residing in the U.S. through the Dravet Syndrome Foundation. Forty-six responses were included in the analysis. Twenty-nine patients (n = 29/46) did not undergo transfer of care - mostly because they were still followed by pediatric neurologists/epileptologists (71%), whereas 17 (n = 17/46) underwent transfer of care. Adult neurology/epilepsy teams providing care never/rarely included a multidisciplinary team (71%), addressed patients' self-advocacy capabilities (53%), or legal guardianship/end-of-life decision-making (59%). Adult neurology/epilepsy teams were considered very much attentive/available (63%), attentive and accommodating to patients with behavioral/cognitive issues (50%), and knowledgeable about caring for patients with intellectual disability/behavioral issues (63%), collaborating with caregivers (75%), and DS - especially in adults (50%). Most caregivers (62.5%) rated the transfer process as good, very good, or excellent. Patients with DS and their caregivers would benefit from more accessible transition programs, which would be ideally equipped to deliver care tailored to these patients' needs.

Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE).

OBJECTIVE: Chromosome 15q duplication (Dup15q) syndrome and cyclin­dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with epileptic encephalopathies, with a lack of specifically approved treatment options. ARCADE assessed the efficacy and safety of adjunctive soticlestat (TAK-935) for the treatment of seizures in patients with Dup15q syndrome or CDD (NCT03694275). METHODS: ARCADE was a phase II, open-label, pilot study of soticlestat (≤300 mg/day twice daily, weight-adjusted) in pediatric and adult patients 2-55 years of age with Dup15q syndrome or CDD who experienced ≥3 motor seizures per month in the 3 months before screening and at baseline. The 20-week treatment period consisted of a dose-optimization period and a 12-week maintenance period. Efficacy endpoints included the change from baseline in motor seizure frequency during the maintenance period and the proportion of treatment responders. Safety endpoints included the incidence of treatment-emergent adverse effects (TEAEs). RESULTS: The modified-intent-to-treat population included 20 participants who received ≥1 dose of soticlestat and had ≥1 efficacy assessment (Dup15q syndrome, n = 8; CDD, n = 12). Soticlestat administration during the maintenance period was associated with a median change from baseline in motor seizure frequency of +11.7% in the Dup15q syndrome group and -23.6% in the CDD group. Reductions in all seizure frequency of -23.4% and -30.5% were also observed during the maintenance period in the Dup15q syndrome group and the CDD group, respectively. Most TEAEs were of mild or moderate severity. Serious TEAEs were reported by three patients (15.0%); none were considered drug related. The most common TEAEs were constipation, rash, and seizure. No deaths were reported. CONCLUSIONS: Adjunctive soticlestat treatment was associated with a decrease in motor seizure frequency from baseline in patients with CDD and a decrease in all seizure frequency in both patient groups. Soticlestat treatment was associated with an increase in motor seizure frequency in patients with Dup15q syndrome.

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism.

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10-15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.

Insights from Spatial Measures of Intolerance to Identifying Pathogenic Variants in Developmental and Epileptic Encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that sometimes lead to death. Although previous work successfully discovered several genes implicated in disease outcomes, it remains challenging to identify causative mutations within these genes from the background variation present in all individuals due to disease heterogeneity. Nevertheless, our ability to detect possible pathogenic variants has continued to improve as in silico predictors of deleteriousness have advanced. We investigate their use in prioritising likely pathogenic variants in epileptic encephalopathy patients' whole exome sequences. We showed that the inclusion of structure-based predictors of intolerance improved upon previous attempts to demonstrate enrichment within epilepsy genes.

A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox-Gastaut syndrome (ELEKTRA).

OBJECTIVE: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452). METHODS: ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs). RESULTS: ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n = 51; LGS, n = 88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p = .0008, n = 139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p = .0002; patients with DS) and 17.08% (p = .1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported. SIGNIFICANCE: Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

Developmental and epileptic encephalopathies: Is prognosis related to different epileptic network dysfunctions?

Developmental and epileptic encephalopathies are a group of rare, severe epilepsies, which are characterized by refractory seizures starting in infancy or childhood and developmental delay or regression. Developmental changes might be independent of epilepsy. However, interictal epileptic activity and seizures can further deteriorate cognition and behavior. Recently, the concept of developmental and epileptic encephalopathies has moved from the lesions associated with epileptic encephalopathies toward the epileptic network dysfunctions on the functioning of the brain. Early recognition and differentiation of patients with developmental and epileptic encephalopathies is important, as precision therapies need to be holistic to address the often devastating symptoms. In this review, we discuss the evolution of the concept of developmental and epileptic encephalopathies in recent years, as well as the current understanding of the genetic basis of developmental and epileptic encephalopathies. Finally, we will discuss the role of epileptic network dysfunctions on prognosis for these severe conditions.

Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort.

OBJECTIVE: This study was aimed to analyze the effectiveness of sodium channel blockers (SCBs) in CDKL5 deficiency disorder (CDD)-related epilepsy. METHODS: A retrospective, observational study was performed, including patients with CDD diagnosis evaluated between 2016 and 2019 at three tertiary Epilepsy Centers. Demographic, electroclinical and genetic features, as well as ASM treatments and their outcomes were analyzed, with special focus on SCBs. RESULTS: Twenty-one patients evaluated at three tertiary Epilepsy Centers were included, of which 19 presented with epilepsy (90.5%); all had pathogenic mutations of CDKL5. Six patients (31.6%) were classified as SCB responders (more than 50% reduction), four being currently seizure free (mean seizure-free period of 8 years). Most frequent SCB drugs were oxcarbazepine (OXC), carbamazepine (CBZ), and lacosamide (LCM). None of them presented relevant adverse events. In contrast, three patients showed seizure aggravation in the non-responder group. When comparing both groups, responders had statistically significant younger age at SCB treatment and epilepsy onset, higher proportion of focal epileptiform activity and less frequent history of West syndrome. CONCLUSIONS: The results of this study indicate that treatment with SCBs might be effective and safe in a subset of patients with CDD-related epilepsy.

Evaluation of the Aberrant Behavior Checklist for Developmental and Epileptic Encephalopathies.

OBJECTIVES: To determine the suitability of the Aberrant Behavior Checklist (ABC)-a common measure used in clinical trials for treatment of challenging behaviors of autism-as an outcome measure for pharmacological and behavioral interventions for young people with Developmental and Epileptic Encephalopathies (DEEs). METHODS: We assessed score profiles on the ABC in a sample of 122 young people with DEEs, including Dravet and Lennox-Gastaut syndromes, and KCNQ2- SCN2A-, and KCNB1-associated disorders. Then we examined its internal structure using item cluster analysis. We used both unrestricted item cluster analysis to determine the number of item clusters that maximize reliability and restricted analyses in which we pre-specified models with 5-, 6-, and 7-clusters, to examine consistency with previous factor analytic studies. We also conducted validity analysis on the various scoring methods with age, sex, and autism spectrum screening measure scores. RESULTS: Unrestricted item cluster analysis suggested that three clusters maximized reliability of ABC scores. These broadly represented other-directed behaviors (i.e., "externalizing"), self-directed behaviors (i.e., "internalizing"), and inappropriate speech. Restricted models separated item clusters for stereotypy from other self-directed problem behaviors, and self-injurious behaviors from the other externalizing behaviors. Validity analysis also supported these structures. Overall, all scores were low, and less than 20% of DEE participants had symptoms severe enough to qualify for most randomized trials of behavioral therapies. SIGNIFICANCE: These results are broadly consistent with the extant ABC scoring algorithms. They suggest a high internal consistency reliability, which may support the use of the ABC in future clinical trials in patients with DEEs who exhibit the behaviors assessed by the ABC. Alternatively, concerns about overall low scores raise cautions about using the ABC as a measure of behavior in unselected populations with DEE.