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Objectives: Developmental and epileptic encephalopathies (DEEs) caused by pathogenic variants in SCN8A are associated with difficult-to-treat and early-onset seizures, developmental delay/intellectual disability, impaired quality of life, and increased risk of early mortality. High doses of sodium channel blockers are typically used to treat SCN8A-DEE caused by gain-of-function (GoF) variants. However, seizures are often drug resistant, and only a few patients achieve seizure freedom. In this retrospective study, the effect of cenobamate was assessed in patients with SCN8A-DEE., Methods: Across multiple centers and through collaborations with SCN8A patient advocacy organizations, patients with SCN8A-DEE treated with cenobamate for ≥6 months were identified. Data were obtained from patients' caregivers or treating physicians through a (Research Electronic Data Capture) REDCap survey. The functional effect of the SCN8A variants was obtained from the literature or assessed by prediction tools., Results: Twelve patients (3-25 years of age (median 8 years), 9 females) with presumed GoF SCN8A variants were treated with cenobamate for a mean period of 17 months (range 6-42 months). Countable motor seizures were meaningfully reduced in 10 of 12 patients (83%). Six patients experienced a seizure reduction above 70%, of which two achieved seizure freedom. In addition, two patients achieved a reduction in seizures ranging between 50% and 70%. An increase in seizure-free days per patient was also reported. Rescue medication was decreased in six of seven patients (85%) in need. Furthermore, 80% of patients reported non-seizure-related improvements, which included increased alertness, better sleep, and improved muscle tone. Adverse effects were reported by 50% of patients, and half resolved spontaneously or through the reduction of concomitant antiseizure medications., Significance: Our data suggest that cenobamate is a promising and safe treatment for SCN8A-DEE, even during early childhood. As a potential precision approach to treatment, cenobamate significantly reduced seizure burden and improved non-seizure-related symptoms. These positive outcomes may also be achieved in patient cohorts with GoF variants in other voltage-gated sodium channel genes., (© 2025 International League Against Epilepsy.)

Knowledge of the natural history of CDKL5 deficiency disorder (CDD) is limited to the results of cross-sectional analysis of largely pediatric cohorts. Assessment of outcomes in adulthood is critical for clinical decision-making and future precision medicine approaches but is challenging because of the diagnostic gap and duration of follow-up that would be required for prospective studies. We aimed to delineate the natural history retrospectively from adulthood. We analyzed clinical data about an international cohort of 67 adults with CDD. We analyzed demographic, phenotypic, CDKL5 Developmental Score (CDS), and treatment data, and tested associations with genetic factors, sex, and a positive or negative history of neonatal seizures, as an early predictor of prognosis. All but one of 67 adults (55 females, median age of 24 years at last follow-up) had epilepsy, typically beginning with epileptic spasms or tonic seizures before 4 months of age. Focal-onset and non-motor seizures emerged later. Fewer than a third had been documented as having bilateral tonic-clonic seizures or status epilepticus. Seizures often improved with age, but 73% had never experienced more than 6 months of seizure-freedom. Clobazam, sodium valproate, and lamotrigine were the most frequently prescribed antiseizure medications, but no specific treatment demonstrated superiority. Common comorbidities included movement disorders, visual impairment, sleep disorders, constipation, and scoliosis. All participants had intellectual disability, 75% had not acquired speech and 45% had regressed developmentally. 16% never achieved any CDS skill, but most attained at least three, and 28% attained six or all seven. By adulthood, half of those who had achieved any CDS skill retained all their CDS skills. The skills most frequently lost were independent walking and standing. Those with a history of neonatal seizures tended to attain fewer CDS skills and were more likely to have abnormal muscle tone in adulthood, atrioventricular conduction delay, and potential complications of their illness and treatment. Individuals carrying missense variants attained more CDS skills than those with other variants and were more likely to lose skills in adulthood and develop anxiety, possibly reflecting the limited neurodevelopment of those with non-missense variants, who manifested a more multisystemic disorder. In summary, retrospective data from adulthood elucidates the evolution of symptoms, variation in developmental outcomes, and the treatment landscape in CDKL5 deficiency disorder. Presence a non-missense variants or a history of neonatal seizures indicates a more complex disorder and lower developmental trajectory. Our findings will inform management decisions, prognostication, and the design of clinical trials in CDKL5 Deficiency Disorder.

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., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: therapeutic equivalence has been established in the effectiveness of peripheral nerve blocks in the management of pain in the postoperative period of anterior cruciate ligament reconstruction. However, it is unknown whether this effect is modulated by the anesthesiologist's experience. The objective was to describe the effectiveness of peripheral nerve blocks during the first 24 hours of the postoperative period, considering patient characteristics and the anesthesiologist's experience., Material and Methods: a retrospective cohort study was conducted from 2015 to 2017. Patients who received a femoral canal block, femoral nerve block, or spinal anesthesia were included. All data were obtained from the patient's medical records, with pain assessed using a visual analog scale recorded in the medical records. A robust, non-parametric kernel regression model was generated to estimate the effect of the variables., Results: out of 480 clinical records, 168 were included in the analysis. The period of greatest pain was between eight and 12 hours, with a non-success rate of up to 22.9%. No differences were found between peripheral nerve blocks. The anesthesiologist's experience did not influence the analgesic effect, while the use of a bone-tendon-bone graft determined greater postoperative pain., Conclusion: in minimally invasive procedures, good pain management outcomes could be observed independently of the anesthesiologist's experience.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

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., (© 2024. The Author(s).)

Objective: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature., Methods: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains., Results: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum., Significance: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy., (© 2024 International League Against Epilepsy.)

Background: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL., Methods: We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed., Results: We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases., Conclusions: Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro-encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern., Methods: In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro-clinical data from 10 epileptic seizures in 5 patients, using prolonged video-EEG monitoring recordings. Inter-ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age- and sex-matched controls., Results: The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro-clinical semiology of seizures was mainly temporal or temporo-insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo-perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions., Interpretation: A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo-insular involvement. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Recording seizures on video-EEG has a high diagnostic value. However, bilateral convulsive seizures constitute a risk for the patients. Our aim was to investigate the diagnostic yield and associated risks of provocation methods in short-term video-EEGs., Methods: We extracted data on seizures and provocation methods from a large database of short-term video-EEGs with standardized annotations using SCORE (Standardized Computer-based Organized reporting of EEG)., Results: 2742 paroxysmal clinical episodes were recorded in 11 919 consecutive EEGs. Most epileptic seizures (54%) were provoked. Hyperventilation provoked most of typical absence seizures (55%), intermittent photic stimulation (IPS) provoked myoclonic seizures (25%) and most of bilateral convulsive seizures (55%), while 43% of focal seizures were precipitated by sleep. All but one of the 16 bilateral convulsive seizures were provoked by IPS or sleep. Latency between start of generalized photoparoxysmal EEG response and bilateral convulsive seizures were ≤3 s in all but one patient., Significance: The large, structured database provides evidence for the diagnostic utility of various provocation methods in short-term video-EEGs. The risk of bilateral convulsive seizures is relatively small, but it cannot be prevented by stopping IPS after 3 s. A priori knowledge about seizure semiology helps planning patient-tailored provocation strategy in short-term video-EEGs., (© 2024 International League Against Epilepsy.)

Pathogenic variants in SCN8A are associated with a broad phenotypic spectrum, including Self-Limiting Familial Infantile Epilepsy (SeLFIE), characterized by infancy-onset age-related seizures with normal development and cognition. Movement disorders, particularly paroxysmal kinesigenic dyskinesia typically arising after puberty, may represent another core symptom. We present the case of a 1-year-old girl with a familial disposition to self-limiting focal seizures from the maternal side and early-onset orofacial movement disorders associated with SCN8A-SeLFIE. Brain MRI was normal. Genetic testing revealed a maternally inherited SCN8A variant [c.4447G > A; p.(Glu1483Lys)]. After the introduction of valproic acid, she promptly achieved seizure control as well as complete remission of strabismus and a significant decrease in episodes of tongue deviation. Family history, genetic findings, and epilepsy phenotype are consistent with SCN8A-SeLFIE. Movement disorders are an important part of the SCN8A phenotypic spectrum, and this case highlights the novel early-onset orofacial movement disorders associated with this condition. The episodes of tongue deviation and protrusion suggest focal oromandibular (lingual) dystonia. Additionally, while infantile strabismus or esophoria is a common finding in healthy individuals, our case raises the possibility of an ictal origin of the strabismus. This study underscores the importance of recognizing and addressing movement disorders in SCN8A-SeLFIE patients, particularly the rare early-onset orofacial manifestations. It adds to the growing body of knowledge regarding the diverse clinical presentations of SCN8A-associated disorders and suggests potential avenues for clinical management and further research., (© 2024 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy., Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician., Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants., Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG., (© 2023 International League Against Epilepsy.)

Background: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia., Methods: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons., Findings: Variants associated with chronic progressive ataxia either decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms., Interpretation: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions., Funding: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen., Competing Interests: Declaration of interests MK reports a doctoral grant from DAAD. JDOE is coordinator of the Chorea and Huntington Disease Group (ERN-RND). EB has received funding from the Dutch Epilepsy Foundation, on behalf of the Dravet syndrome Foundation Netherlands/Flanders, the JANIVO foundation and the K.F. Hein Foundation. LS declares grants from the German Research Foundation, German Ministry of Heath, European Commission, and Innovationsfond, and has received consulting fees from Vico Therapeutics and Novartis. RSM has received consulting and speaker fees from UCB and Orion and speaker fees from EISAI and Angelini Pharma. All other authors report no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10 -9 ) and 10p11.21 (P = 3.6 × 10 -8 ). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10 -3 ). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10 -3 ) and increased seizure-like events (P = 6.8 × 10 -7 ). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10 -3 ). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease., (© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.)