BACKGROUND:Abusive head trauma (AHT) in children is challenging to diagnose due to unreliable histories and varying presentations and findings from additional examinations. Findings from additional examinations may help distinguish AHT from non-abusive head trauma (nAHT), but single studies report conflicting results. OBJECTIVE:This systematic review (SR) synthesizes evidence on differences in additional examinations between children under 2 years with AHT and nAHT. METHODS:We searched Ovid Medline, Web of Science, and the Cochrane Library for comparative observational studies to identify differences in cerebral, spinal, ophthalmological and skeletal findings between children with AHT and nAHT. Two reviewers independently selected studies, extracted data, and assessed risk of bias (RoB) using the Newcastle-Ottawa Scale. Random-effects meta-analyses and sensitivity analyses were performed. RESULTS:Forty (mostly retrospective) studies reported 51 clinical variables. Eighteen variables were associated with AHT: subdural hemorrhage (SDH), bilateral SDH, interhemispheric blood, mixed-density SDH, multilayered SDH, any intracranial hemorrhage (ICH), ICH without skull fracture, cerebral edema, ischemia, and atrophy, hydrocephalus, spinal SDH, cervical and thoracolumbar spinal SDH, retinal hemorrhages (RH), bilateral RH, vitreous hemorrhage and skeletal fracture. The variables skull fracture, isolated skull fracture, epidural hemorrhage (EDH), subgaleal hematoma, and long bone fracture were associated with nAHT. Moderate or high RoB was observed in 69% of the assessments. CONCLUSIONS:Certain cerebral, spinal, ophthalmological and skeletal features in children under 2 years with head injury may indicate AHT, with potential implications for accurate diagnosis and timely safeguarding. Results should be interpreted cautiously given the moderate to high RoB in the majority of assessments.

Loss-of-function (LOF) variants in KCNQ2, encoding the potassium channel subunit Kv7.2, cause a spectrum of neonatal epilepsies ranging from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). To dissect the developmental consequences of Kv7.2 LOF, we conducted a longitudinal and multimodal comparative analysis in a human neuronal model generated from patients with KCNQ2-DEE and KCNQ2-SeLFNE. KCNQ2-LOF variants induced a biphasic dysfunction at both single-cell and network levels, characterized by early Kv7-driven hyperexcitability accompanied by a clear reduction M-current density, which was rescued by acute Retigabine treatment. At later stages, intrinsic excitability and M-current normalized, yet network activity diverged further from control trajectories, indicating compensatory and ultimately maladaptive network remodeling. Transcriptomic analysis mirrored this biphasic dynamic trajectory, revealing an initial upregulation followed by a subsequent downregulation of synaptic genes. Structural analysis showed a steeper decline in presynaptic density alongside a distal shift in the axon initial segment (AIS) throughout maturation, and impaired AIS plasticity at later stages. Overall, KCNQ2-LOF variants disrupt human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options.

Chromatin regulation is critical for neurodevelopment, and its disruption has emerged as a key pathogenic mechanism in neurodevelopmental disease, including autism spectrum disorder (ASD), a condition known for genetic and phenotypic heterogeneity. We previously identified an ASD gene, KDM5A, encoding a histone H3 lysine 4 demethylase, and reported de novo and inherited variants in nine individuals with severe ASD and other neurodevelopmental phenotypes. Here, we expand the genetic and phenotypic spectrum of KDM5A-related neurodevelopmental disorders and investigate the functional impact of identified variants. Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features. The variants include missense, nonsense, frameshift, and splice site, distributed across nearly all functional domains of the protein. Structural modeling revealed localized conformational disruptions, particularly at conserved residues in enzymatic or chromatin-interacting domains. For a subset of variants, we demonstrated reduced KDM5A protein levels in cell lines derived from affected individuals. Transcriptomic profiling revealed variant-specific gene expression changes, most pronounced in variants affecting the PLU1 chromatin binding motif and the Jumonji C domain of the enzymatic core. American College of Medical Genetics and Genomics-guided reclassification supported pathogenicity for the majority of variants, including multiple upgrades from uncertain significance to pathogenic or likely pathogenic. Together, these findings implicate diverse KDM5A alleles in a rare but recurrent form of ASD, and establish KDM5A as a key regulator of neurodevelopment and chromatin-mediated ASD pathogenesis.

CMIP, a c-maf inducing protein that plays a key role in cytoskeletal remodeling, neuronal migration and synaptic formation, was first associated with specific language impairment and autism through the identification of a deletion in a single patient in 2012. Since then, only two additional individuals with CMIP deletions have been reported, both sharing features of autism and gastrointestinal features. However, a firm causal relationship between variants in CMIP and neurodevelopmental disorders has not yet been established. In this multicentre cohort study, we identified 25 individuals, from 17 unrelated families, with CMIP-related neurodevelopmental disorders, 22 of whom have not been previously reported. Of these, seven individuals carried heterozygous loss-of-function CMIP single-nucleotide variants, while the other 18 individuals had a complete or partial deletion of CMIP, some involving adjacent genes. The clinical phenotype was variable with a high prevalence of developmental delay (20/25), autism spectrum disorder features (13/25), attention-deficit/hyperactivity disorder features (11/25) and other psychiatric disorders (15/25). Epilepsy was present in nine individuals (9/25), of whom three had therapy-resistant seizures. To study the pathogenicity of CMIP variants, a cmip mutant zebrafish model carrying a premature stop codon was investigated. These mutants showed temperature-dependent altered locomotor activity suggestive of seizure-like behavior, which was confirmed by spontaneous epileptiform discharges in cmip+/- mutant zebrafish larvae. Our patient cohort and the zebrafish data establish CMIP as a gene implicated in neurodevelopmental and neuropsychiatric disorders. We recommend inclusion of CMIP in the genetic work-up of neurodevelopmental delay, with or without autism or psychiatric disorders and epilepsy.

OBJECTIVE:Precision medicine (PM) is gaining increasing importance in the treatment of rare genetic epilepsies. However, its availability and implementation in clinical practice remain limited. This study explores the barriers and facilitators influencing the implementation of PM for people with epilepsy (PWE). METHODS:Semistructured interviews were conducted with clinicians involved in epilepsy care for PWE across various global regions. Participants were purposefully selected based on geographical distribution and World Bank income classification. Framework analysis was used to identify key themes. RESULTS:Sixteen clinicians from six different continents were interviewed. Five key themes emerged. The implementation of PM depends on (1) the personal perspective and experience of health care providers; (2) the attitude of PWE and their caregivers toward PM, and their interaction with clinicians; (3) continuous education of health care providers, formation of expert teams, and generation of robust evidence on PM; (4) multilevel collaboration including patient advocacy groups; and (5) a clear, consistent organizational approach and the development and implementation of standardized guidelines. SIGNIFICANCE:Clinicians consider PM as transformative for the care for PWE and expect it to redefine standard practice in the near future. Insufficient knowledge is the primary barrier to PM implementation, irrespective of socioeconomic context, highlighting the need for its integration into basic medical training and residency programs. To address inequities, integrated care pathways and standardized guidelines for genetic testing and PM, and the establishment of local PM-focused expert teams are essential to support clinicians in making informed PM decisions.

OBJECTIVE:Heterozygous gain-of-function (GOF) variants in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channel subunits Kv7.2 and Kv7.3, lead to neurodevelopmental disorders for which no established treatments are available. Amitriptyline, an antidepressant, blocks Kv7.2/Kv7.3 and has previously been reported to be effective in a single individual with a KCNQ2 GOF variant. We designed a retrospective, single-arm, multicenter study to investigate the effects of amitriptyline in a real-world setting. METHODS:We used a 7-point Likert scale to measure seizure frequency, clinical examination, motor function, alertness, skill acquisition, communication, mood, behavior, self-care, sleep, tiredness, and electroencephalogram at baseline, after a minimum of 6 weeks of intervention, and, if applicable, after discontinuation. Adverse events were assessed in all participants, and the effectiveness of the treatment was evaluated in 11 individuals who received a minimum dosage of .5 mg/kg/day for at least 6 weeks. Data were collected from October 2023 to August 2024. RESULTS:Thirteen individuals, eight with a pathogenic KCNQ2 GOF variant and five with a pathogenic KCNQ3 GOF variant, were included. Nine were female, and the median age at start of amitriptyline was 7.1 years (range = 1.5-20 years). Eleven individuals received a minimum dosage of .5 mg/kg/day for at least 6 weeks. The median dosage of amitriptyline administered was 1 mg/kg/day, with a median treatment duration of 29 weeks. Although amitriptyline was ineffective in two individuals (18%), eight (72%) demonstrated at least minimal improvement in two or more domains, with improvements in alertness and communication being the most frequently reported. In those with reported improvements, amitriptyline was discontinued in four individuals, but continued improvements were seen, to the same or greater extent compared to treatment. The remaining five individuals are on continued treatment because of perceived benefits. SIGNIFICANCE:Overall, the effect of amitriptyline remains unclear, and formal n-of-1 trials are needed to investigate the precise effects of amitriptyline in KCNQ GOF-related neurodevelopmental disorders.

BACKGROUND:Abusive head trauma (AHT) is challenging to diagnose due to unreliable histories and unrecognized clinical features. OBJECTIVE:To synthesize evidence on the association between reported clinical features and the likelihood of AHT versus non-abusive head trauma (nAHT) in children under 2 years with head injury. METHODS:We searched Ovid Medline, Web of Science, and the Cochrane Library (18/12/2020; updated 17/9/2023). Two reviewers independently selected studies, extracted data, and assessed risk of bias using the Newcastle-Ottawa Scale. Random-effects meta-analyses with forest plots and sensitivity analyses were performed. RESULTS:Twenty variables were identified in 27 studies, mainly retrospective cohorts. Seven variables were associated with AHT: evidence of old injury (OR 40.42 [95 % CI 7.53; 216.93]), apnea or hypoventilation (OR 14.23 [95 % CI 5.26; 38.48]), history of upper respiratory tract infection/distress (OR 11.96 [95 % CI 1.56; 92.02]), external injury excluding head (OR 5.80 [95 % CI 2.20; 15.31]), seizures (OR 5.65 [95 % CI 2.95; 10.81]), abnormal mental status (OR 3.98 [95 % CI 1.20; 13.18]), and a higher Injury Severity Score (median difference 9.34 [95 % CI 6.41; 12.27]). External head injury (OR 0.24 [95 % CI 0.09; 0.63]) and asymptomatic presentation (OR 0.03 [95 % CI 0.01; 0.18]) were associated with nAHT. Sensitivity analysis identified associations of unconsciousness (OR 3.68 [95 % CI 1.50; 9.03]) and cardiopulmonary arrest (OR 10.53 [95 % CI 1.35; 82.05]) with AHT, and of bruising (OR 0.27 [95 % CI 0.10; 0.71]) with nAHT. Moderate or high risk of bias was observed in 62 % of the assessments. CONCLUSIONS:Certain clinical features in children under 2 years with head injury may indicate AHT. Results should be interpreted cautiously given the moderate to high risk of bias in the majority of assessments.

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmacoresistant seizures and developmental delay. Patients with DEEs experience multiple seizure types, including tonic-clonic seizures (TCS) that can be generalized tonic-clonic (GTCS) or focal evolving to bilateral tonic-clonic (FBTCS). Fenfluramine (FFA) has demonstrated efficacy in reduction of TCS in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and other DEEs. Using the PRISMA-ScR (Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Review) guidelines, we performed a scoping review to describe changes in TCS in patients treated with FFA. A comprehensive search of five literature databases was conducted up to February 14, 2023. Studies were included if they reported change in GTCS or TCS (but not FBTCS) after treatment with FFA in patients with DEEs. Duplicate patients and studies with unclear efficacy data were excluded. Fourteen of 422 studies met the eligibility criteria. Data extracted and evaluated by expert clinicians identified 421 unique patients with DS (in nine studies), CDKL5 deficiency disorder, SCN8A-related disorder, LGS, SCN1B-related disorder, and other DEEs. The median percent reduction in GTCS or TCS from baseline was available in 10 studies (n = 328) and ranged from 47.2% to 100%. Following FFA treatment, 10 studies (n = 144) reported ≥50% reduction in GTCS or TCS from baseline in 72% of patients; in nine of those (n = 112), 54% and 29% of patients achieved ≥75% and 100% reduction in GTCS or TCS from baseline, respectively. Overall, this analysis highlighted improvements in GTCS or TCS frequency when patients were treated with FFA regardless of the DEE evaluated. Future studies may confirm the impact of FFA on TCS reduction and on decreased premature mortality risk (including sudden unexpected death in epilepsy), improvement in comorbidities and everyday executive function, decreased health care costs, and improvement in quality of life.

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1 variants and three new individuals with de novo PCBP2 variants. Our findings add additional evidence for LEO1 as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2 as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.

The implementation of whole exome sequencing (WES) has had a major impact on the diagnostic yield of genetic testing in individuals with epilepsy. The identification of a genetic etiology paves the way to precision medicine: an individualized treatment approach, based on the disease pathophysiology. The aim of this retrospective cohort study was to: (1) determine the diagnostic yield of WES in a heterogeneous cohort of individuals with epilepsy referred for genetic testing in a real-world clinical setting, (2) investigate the influence of epilepsy characteristics on the diagnostic yield, (3) determine the theoretical yield of treatment changes based on genetic diagnosis and (4) explore the barriers to implementation of precision medicine. WES was performed in 247 individuals with epilepsy, aged between 7 months and 68 years. In 34/247 (14 %) a (likely) pathogenic variant was identified. In 7/34 (21 %) of these individuals the variant was found using a HPO-based filtering. Diagnostic yield was highest for individuals with an early onset of epilepsy (39 %) or in those with a developmental and epileptic encephalopathy (34 %). Precision medicine was a theoretical possibility in 20/34 (59 %) of the individuals with a (likely) pathogenic variant but implemented in only 11/34 (32 %). The major barrier to implementation of precision treatment was the limited availability or reimbursement of a given drug. These results confirm the potential impact of genetic analysis on treatment choices, but also highlight the hurdles to the implementation of precision medicine. To optimize precision medicine in real-world practice, additional endeavors are needed: unifying definitions of precision medicine, establishment of publicly accessible databases that include data on the functional effect of gene variants, increasing availability and reimbursement of precision therapeutics, and broadening access to innovative clinical trials.

Purpose: Cerebral palsy (CP) is the most frequent cause of motor impairment in children. While perinatal asphyxia was long considered to be the leading cause of CP, recent studies demonstrate its causation in only around 1 in 10 individuals with CP. Instead, genetic causes are increasingly demonstrated. We systematically performed clinical phenotyping and genetic investigations in a monocentric CP cohort, aiming to gain insight into the contribution of genetic variants in CP and its different subtypes. Methods: Chromosomal microarray and/or trio exome sequencing were systematically performed in 337 individuals with CP between September 2017 and August 2022. Deep phenotyping was performed through clinical multidisciplinary evaluation and review of medical files. Results: Genetic analyses resulted in an overall diagnostic yield of 38.3% (129/337). In cases with one or more comorbidities (intellectual disability, epilepsy, autism spectrum disorder), the yield increased to almost 50%. Functional enrichment analysis showed overrepresentation of the following pathways: genetic imprinting, DNA modification, liposaccharide metabolic process, neuron projection guidance and axon development.Conclusion: Genetic analyses in our CP cohort, the largest monocentric study to date, demonstrated a diagnostic yield of 38.3%, highlighting the importance of genetic testing in CP. The diagnosis of a genetic disorder is essential for prognosis and clinical follow-up, as well as for family counseling. Pathway analysis points to dysregulation of general developmental and metabolic processes as well as neuronal development and function. Unravelling the role of these pathways in CP pathogenesis is instrumental for identification of CP candidate genes as well as potential therapeutic targets.

OBJECTIVE:SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood.METHODS:We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype.RESULTS:DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS.SIGNIFICANCE:Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.

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.

OBJECTIVE:This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. METHODS:This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. RESULTS:A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. SIGNIFICANCE:The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.

OBJECTIVE:Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS:Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS:Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION:Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.

Background and ObjectivesBRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.DiscussionBRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

Objective: We aim to describe the effectiveness of fenfluramine (FFA) on generalized tonic-clonic seizures (GTCS) in patients with rare epilepsy syndromes. Background: Seizure refractoriness and frequent GTCS are hallmarks of developmental and epileptic encephalopathies (DEEs) and are 2 major risk factors for sudden unexpected death in epilepsy (SUDEP). Patients with 1–3 GTCS/year have up to a 16-fold greater risk of SUDEP. An analysis of SUDEP rates in patients with Dravet syndrome (DS) found a 5-fold lower SUDEP mortality rate in FFA-treated patients compared to historical controls. FFA has demonstrated reduced seizure burden in other rare epilepsies. Design/Methods: Studies where FFA was used to manage convulsive seizures associated with rare epilepsy syndromes were included. Initial FFA doses, duration of treatment (exposure) and reduction in GTCS or tonic-clonic seizures (TCS) are reported. Descriptive statistics were used. Results: We included data from 13 studies: 4 randomized-controlled trials (RCTs), 4 observational studies, 4 open-label studies, and 1 case series. In these studies, 561 patients were treated with FFA for DS (n=360), LGS (n=176), Sunflower syndrome (n=10), CDKL5 deficiency disorder (n=6), SCN8A-related disorder (n=3), and other DEEs (n=6). Of these, 396 (70.6%) patients experienced GTCS or TCS at baseline. FFA was generally initiated at 0.2 mg/kg/day and titrated per protocol or physician discretion; FFA exposure: 14 weeks–27 years. In 8 studies, the median percent reduction in GTCS ranged from 45.7%–90.8%. Among 8 studies, 7 reported at least half of the patients experienced ≥75% reduction in GTCS (or TCS); five studies reported more than half of patients were GTCS-free after FFA treatment. Conclusions: These results indicate that FFA led to a clinically significant reduction in GTCS (or TCS) frequency in patients with rare epilepsy syndromes, suggesting it may also reduce SUDEP rates in these disorders. Further research is needed to determine the impact of FFA on SUDEP in those patient populations. Disclosure: Dr. Cross has nothing to disclose. Dr. Devinsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Devinsky has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for California Cannabis Enterprises. Dr. Devinsky has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Engage. Dr. Devinsky has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Privateer Holdings. Dr. Devinsky has received personal compensation in the range of $1,000,000+ for serving on a Scientific Advisory or Data Safety Monitoring board for Receptor Holdings. Dr. Devinsky has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Rettco. Dr. Devinsky has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Silver Spike. Dr. Devinsky has received personal compensation in the range of $100,000-$499,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Tevard. Dr. Devinsky has received personal compensation in the range of $1,000,000+ for serving on a Scientific Advisory or Data Safety Monitoring board for Tilray. Dr. Devinsky has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Engage. Dr. Devinsky has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Tevard Biosciences. Dr. Devinsky has received stock or an ownership interest from Engage. Dr. Devinsky has received stock or an ownership interest from Empatica. Dr. Devinsky has received stock or an ownership interest from California Cannabis Enterprises. Dr. Devinsky has received stock or an ownership interest from Empatica. Dr. Devinsky has received stock or an ownership interest from Silver Spike. Dr. Devinsky has received stock or an ownership interest from Docklight Brands. Dr. Devinsky has received stock or an ownership interest from Egg Rock/Papa Barkley. Dr. Devinsky has received stock or an ownership interest from Leafly. Dr. Devinsky has received stock or an ownership interest from Left Coast Ventures. Dr. Devinsky has received stock or an ownership interest from Privateer Holdings. Dr. Devinsky has received stock or an ownership interest from Receptor Holdings. Dr. Devinsky has received stock or an ownership interest from Qstate. The institution of Dr. Devinsky has received research support from GW Pharma. The institution of Dr. Devinsky has received research support from Zogenix. The institution of Dr. Devinsky has received research support from PTC Pharma. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from DOD. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from Epilepsy Foundation. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from NSF. Dr. Devinsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Devinsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Devinsky has received publishing royalties from a publication relating to health care. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $0-$499 for serving as a Consultant for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zogenix . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIAL . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Jazz Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zogenix . The institution of Dr. Gil-Nagel has received research support from Jazz Pharmaceuticals. The institution of Dr. Gil-Nagel has received research support from PTC Therapeutics. The institution of Dr. Gil-Nagel has received research support from Zogenix. The institution of Dr. Gil-Nagel has received research support from Agencia Estatal Innovacion. The institution of Berten Ceulemans has received personal compensation in the range of $500-$4,999 for serving as a Consultant for zogenix. The institution of Berten Ceulemans has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for zogenix. Berten Ceulemans has received intellectual property interests from a discovery or technology relating to health care. Dr. Lagae has nothing to disclose. Dr. Knupp has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for zogenix. Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for encoded. Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for stoke. The institution of Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW pharmaceuticals. Dr. Knupp has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsy Research. An-Sofie Schoonjans has nothing to disclose. Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arvelle/Angelini. The institution of Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB pharma. The institution of Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Angelini pharma. The institution of Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB pharma. The institution of Dr. Ryvlin has received research support from Swiss National Fund. The institution of Dr. Ryvlin has received research support from European Commission (Horizon Europe). Dr. Thiele has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for GW Pharma. Dr. Thiele has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for zogenix. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aquestive. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for West Therapeutics. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RegenxBio. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for nobelpharma. An immediate family member of Dr. Thiele has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Thor labs. Dr. Thiele has received personal compensation in the range of $0-$499 for serving as a Consultant for Biocodex. The institution of Dr. Thiele has received research support from GW Pharma. The institution of Dr. Thiele has received research support from Zogenix. Rima Nabbout has nothing to disclose. Dr. Lothe has received personal compensation for serving as an employee of UCB. Dr. Lothe has received personal compensation for serving as an employee of Zogenix International Limited. Dr. Lothe has stock in Zogenix . Shikha Polega has received personal compensation for serving as an employee of UCB. Shikha Polega has stock in UCB. Shikha Polega has stock in Zogenix.