Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS) represents a rare but severe group of childhood onset epilepsies characterized by sleep-potentiated epileptiform activity, seizures, and developmental stagnation or regression affecting cognition, language, and behavior. Once considered a self-limited electroencephalographic (EEG) phenomenon, D/EE-SWAS is now recognized as a disorder of brain network dysfunction in which persistent epileptiform discharges during non-rapid eye movement sleep disrupt synaptic plasticity, sleep-dependent memory consolidation, and neurodevelopmental trajectories. This review synthesizes recent advances in clinical phenotyping, genetics, neurophysiology, and therapeutics. Etiologically, D/EE-SWAS is highly heterogeneous, with pathogenic variants identified in nearly half of affected individuals, including copy number variants and single-gene disorders involving ion channels, synaptic proteins, and transcriptional regulators. GRIN2A is the most frequently implicated gene, although marked intrafamilial and interfamilial variability underscores the role of modifying genetic and network-level factors. Structural lesions-particularly those affecting thalamocortical circuits-represent another major disease substrate and are critical for treatment stratification. At the mechanistic level, abnormal thalamocortical oscillations, impaired sleep architecture, and disruption of slow-wave and spindle activity provide a pathophysiological framework linking EEG abnormalities to cognitive and behavioral deterioration. Neuroimaging and EEG-functional magnetic resonance imaging studies support a model of widespread network inhibition and disconnection extending beyond the primary epileptogenic zone. Therapeutically, corticosteroids currently represent the most effective first-line treatment, demonstrating superior cognitive outcomes compared with benzodiazepines, although relapse after tapering is common, and optimal dosing strategies remain undefined. Precision medicine approaches, including N-methyl-D-aspartate receptor-targeted therapies for GRIN variants and channel-specific treatments such as primidone for TRPM3 gain of function, offer promising avenues toward disease modification. Epilepsy surgery should be considered early in children with unilateral structural etiologies, where it can provide substantial neurodevelopmental benefit. Future priorities include standardized outcome measures, integration of sleep-based biomarkers, refinement of steroid protocols, and international collaborative trials to improve long-term neurodevelopmental outcomes in this vulnerable population.

Children with developmental and epileptic encephalopathies (DEEs) face cognitive and behavioral challenges that may have a greater impact than seizures on their quality of life (QoL). The need to assess these nonseizure outcomes for evaluating treatments is increasingly recognized. Advances in genomic technologies have transformed the diagnostic landscape of rare genetic epilepsies, including DEEs, opening new opportunities for precision medicine. There is also growing interest in drug repurposing, identifying well-tolerated medications for other indications for use in DEEs. Innovative trial designs and the systematic collection of prospective natural history data are essential, given the rarity and heterogeneity of DEEs. The selection of reliable, valid, and meaningful outcome measures of cognition and behavior is crucial for clinical trials and natural history studies. Commonly used tools for assessing cognition and adaptive behavior often exhibit floor effects and may fail to capture subtle, yet clinically significant, changes in functioning that are meaningful for children and their families. There is thus a need to explore a fuller range of clinical outcome assessments (COAs) and scoring methods that could be sensitive to change and suitable for use in rare disease populations. Assessing behavioral and emotional outcomes in children with DEEs is additionally challenging, as many assessment instruments have been developed and validated for use in children without intellectual disability. To fully realize the potential of precision medicine in the DEEs, a robust framework for outcomes assessment is required, one that incorporates sensitive, reliable, and meaningful COAs tailored to this population. Coordinated efforts to identify and adapt existing measures or develop new outcome tools will be crucial for advancing therapeutic strategies that genuinely improve QoL for children with DEEs. This article summarizes the issues faced when selecting outcome measures for DEE trials and reviews commonly used instruments for assessing cognition and behavior in children with DEEs.

OBJECTIVE:Genetic testing plays an increasing role in the diagnostic pathway for rare and complex epilepsies. However, significant heterogeneity persists in access, implementation, and interpretation across Europe. This study aimed to assess genetic testing practices, accessibility, and challenges across expert epilepsy centers within the European Reference Network for Rare and Complex Epilepsies (ERN EpiCARE) and to identify key challenges and areas for harmonization. METHODS:A cross-sectional survey was developed by the ERN EpiCARE Clinical Genetics Working Group and distributed to 50 EpiCARE member centers across 27 European countries. The questionnaire collected quantitative and qualitative information on available genetic testing modalities, turnaround times, use of rapid testing, multidisciplinary team (MDT) organization, genetic counseling practices, and perceived challenges. Survey findings were complemented by a structured discussion held during the ERN EpiCARE General Assembly. RESULTS:Responses were received from 46 centers (51 responses). Most centers reported access to genetic testing, predominantly through in-house facilities. Whole-exome sequencing was available in 85% of centers, and gene panels were available in 78%. Whole-genome sequencing was available in 59% of centers, frequently restricted to research or performed externally. Turnaround times for standard genetic testing were most commonly between 1 and 6 months. Genetic testing strategies varied by epilepsy subtype, with gene panels most frequently used as first-tier testing, and exome sequencing preferentially applied in developmental and epileptic encephalopathies. Considerable heterogeneity was observed in MDT organization, access to genetic counseling, reimbursement, data-sharing and registry infrastructures. SIGNIFICANCE:Although genetic testing is widely available across ERN EpiCARE centers, substantial disparities persist in its organization, accessibility, and implementation. Addressing these gaps through strengthened multidisciplinary collaboration, harmonized diagnostic strategies, and enhanced European-level coordination will be essential to ensure equitable access to high-quality genetic care for individuals with epilepsy. PLAIN LANGUAGE SUMMARY:Genetic testing is increasingly integrated in the diagnostic pathway for rare and complex epilepsies and treatment decisions. An ERN EpiCARE survey assessed how genetic testing is implemented across specialist epilepsy centers in Europe and identified persistent organizational, financial, and clinical barriers. Although most centers had access to advanced genomic testing, important differences were identified in access, reimbursement, turnaround times, and multidisciplinary expertise. European collaboration and harmonized practices are needed to support equitable access to high-quality genetic care for people living with epilepsy.

BACKGROUND:Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels, in patients with Dravet syndrome are not known. METHODS:We enrolled patients 2 to 18 years of age with Dravet syndrome who were receiving standard antiseizure medications in two phase 1-2a, open-label, multicenter studies (MONARCH and ADMIRAL). Patients were included in either a single-ascending-dose cohort, in which zorevunersen (10 to 70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period. Patients eligible for rollover to the two open-label extension studies (SWALLOWTAIL and LONGWING) continued to receive zorevunersen (≤45 mg) every 4 months. The safety and pharmacokinetics of zorevunersen were assessed in the primary analysis; clinical effects were also evaluated. RESULTS:A total of 81 patients were enrolled in the phase 1-2a studies. As of May 30, 2025, a total of 75 patients had entered the extension studies. Most adverse events were mild or moderate. The most common adverse event was post-lumbar puncture syndrome (in 25% of patients) in the phase 1-2a studies and was an elevated protein level in cerebrospinal fluid (in 45%) in the extension studies. One patient had suspected unexpected serious adverse reactions, 1 had an adverse event that led to study withdrawal, 2 died from sudden unexpected death in epilepsy, and 1 died from malnutrition. Patients who received 70 mg of zorevunersen (one, two, or three doses) in the phase 1-2a studies, followed by up to 45 mg in the extension studies, had a median change from baseline in convulsive-seizure frequency ranging from -58.82% to -90.91% across 1-month intervals during the first 20 months of the extension studies. The data supported improvements in overall clinical status, quality of life, and adaptive behavior with continued treatment for up to 36 months in the extension studies. CONCLUSIONS:The safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome. (Supported by Stoke Therapeutics; MONARCH and SWALLOWTAIL ClinicalTrials.gov numbers, NCT04442295 and NCT04740476, respectively; ADMIRAL and LONGWING ISRCTN Registry numbers, ISRCTN99651026 and ISRCTN12811235, respectively.).

Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework's utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

OBJECTIVE:To define and articulate research priorities in epilepsy identified by the European Reference Network for Rare and Complex Epilepsies (ERN EpiCARE), addressing key unmet needs across the spectrum of rare and complex epilepsies. METHODS:This position paper was developed through a structured collaborative process involving patient associations and experts from EpiCARE Working Groups, the EpiCARE Executive Committee, and its Research Council. Contributions were integrated and harmonized to establish a shared set of research priorities reflecting clinical, translational, and methodological perspectives. RESULTS:Six priority areas were identified and examined: prevention of epileptogenesis and disease-modifying challenges; genetics and targeted therapies; improved surgical decision-making; innovative trial designs and outcome measures; artificial intelligence for diagnosis and prediction; understanding and preventing comorbidities and mortality. For each priority, the paper discusses the current state of research, identifies challenges, and proposes strategic directions for future investigations. SIGNIFICANCE:This position paper provides a strategic framework to guide future research efforts, inform prioritization by funders and policymakers, and foster coordinated collaboration across stakeholders. By advancing these priorities, the epilepsy research community aims to improve patient care, reduce health disparities, and develop innovative solutions to address the complexities of epilepsy. PLAIN LANGUAGE SUMMARY:This position paper, developed by the European Reference Network for Rare and Complex Epilepsies (EpiCARE) in collaboration with its Patient Advocacy Group, defines six areas of research priorities in epilepsy. Each section describes key challenges, current knowledge, and areas for improvement. They focus on preventing epilepsy, developing targeted therapies, improving surgery and clinical trials, using artificial intelligence to support diagnosis, and addressing comorbidities such as cognition, sleep, and overall health. Each provides a roadmap for clinicians and researchers to guide their research projects within their areas of expertise. Collectively, these priorities converge on actions for improving diagnosis, treatment, and patient outcomes through European collaboration and sustainable research efforts.

Objective Neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis (NDEEMA) represents the most severe end of the gain-of-function (GOF) SCN1A disorder spectrum. Sporadic cases of congenital arthrogryposis have also been reported in individuals with SCN2A-, SCN3A-, and SCN8A-related developmental and epileptic encephalopathy. Here, we investigated whether NDEEMA occurs in other brain-expressed sodium channelopathies and characterized its features.Methods Individuals with the clinical phenotype of NDEEMA were identified through internal databases, an international network of epileptologists and geneticists, and the literature. Their clinical and genetic information was analyzed. A literature survey was conducted to review studies describing the functional effects of the pathogenic variants.Results Of 46 NDEEMA individuals, 25 harbored variants in SCN1A, 13 in SCN2A, one in SCN3A, and seven in SCN8A. Thirty-five different pathogenic/likely pathogenic missense variants were identified, all of which clustered in evolutionary conserved paralogous NaV positions. Five individuals died in utero. Thirty-nine of 41 (95%) liveborn individuals developed neonatal epilepsy with tonic seizures and/or apnea. Thirty-one individuals tried sodium channel blockers, of whom 21 (68%) experienced seizure reduction. All individuals for whom information was available developed movement disorders, with myoclonus, dystonia, and tremor being the most common features. Literature review of functional studies revealed that nine NDEEMA variants, and the corresponding paralogues of 16 additional NDEEMA variants, have been biophysically characterized as GOF.Significance This study expands the phenotype of NDEEMA from SCN1A to its paralogue sodium channel genes expressed in the brain: SCN2A, SCN3A, and SCN8A.

Background and Objectives Elicited Repetitive Daily Blindness (ERDB) is a debilitating condition resulting in recurrent, daily episodes of reversible visual loss. ERDB has been described in individuals with Familial Hemiplegic Migraine 3 (FHM3), caused by pathogenic SCN1A variants. Two families with cosegregation of FHM3 and ERDB (families 1-2) have previously been reported associated with SCN1A variants c.4467G > C/p.(Q1489H) and c.4495T > C/p.(F1499L). However, F1499L was also identified in a separate FHM3 family without ERDB. Thus, it is uncertain whether ERDB is a clinical feature in FHM3 besides the 2 identified families. We present 4 new families with cosegregation of FHM3 and ERDB resulting from 3 novel SCN1A variants. The proband in each family was commenced on sodium channel blocker medication. We performed functional analysis of the previously reported Q1489H and F1499L variants, including the overall effect in GABAergic neurons. Methods Data were collated through clinical interview and review of medical records for the probands of 4 new families with FHM3 and ERDB. Genetic analysis was performed for probands and, where possible, their parents. Whole-cell patch-clamp experiments were performed to measure sodium currents. Measurements were taken from transfected temperature sensitive SV40 Large T-antigen (tsA-201) cells and cortical GABAergic neurons in primary culture expressing the human Nav1.1 voltage-gated sodium channel with either wild type (WT), Q1489H, or F1499L variants. Results Four new pedigrees are described with typical FHM3 and ERDB (families 3-6). Blindness attacks commenced from infancy to 9 years of age. Episodes occurred 3-10 times per day, lasting up to 30 seconds. Genetic testing revealed novel heterozygous variants in the SCN1A gene for family 3 (c.4027G > T/p.[A1343S]), 4 (c.5350G > T/p.[V1784F]), 5 (c.5006C > T/p.[A1669F]) and 6 (c.5006C > T/p.[A1669F]). Electrophysiologic testing revealed an overall gain-of-function on Nav1.1-mediated currents for the previously reported variants Q1489H and F1499L when compared with WT, particularly when they were expressed in cortical GABAergic neurons. In silico tools predicted gain-of-function in the 3 novel variants. All 4 probands responded well to treatment with carbamazepine reporting fewer migraines and blindness episodes. Discussion Our study demonstrates that ERDB is a clinical feature in FHM3 patients because of gain-of-function Nav1.1 variants. Patients in this report responded to sodium channel blocker medications.

OBJECTIVE:Dravet syndrome (DS) is the prototypic developmental and epileptic encephalopathy, characterized by drug-resistant seizures, developmental slowing, and many other morbidities. Detailed characterization of behavioral phenotypes and social-emotional skill development are limited. METHODS:We prospectively assessed behavioral and social-emotional problems in the ENVISION natural history study (NCT04537832) of children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at <5 years of age. Assessments every 3 months for up to 2 years included the Child Behavior Checklist (CBCL), Strengths and Difficulties Questionnaire (SDQ), Brief Infant-Toddler Social and Emotional Assessment (BITSEA), and Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3). RESULTS:Fifty-eight children with DS enrolled at 16 sites worldwide. Problematic behaviors-inattention, aggressive or oppositional behaviors, and withdrawn and autistic behaviors-began before age 3 years, became more evident with age, and were clinically significant in many children by age 3-4 years. CBCL Total, Externalizing, and Internalizing Problems T-scores rose by approximately 3 points per year, and BITSEA Problem scale scores increased by 2.3 points annually (p = .002). SDQ Hyperactivity scores worsened over time (p = .013), whereas emotional difficulties remained stable. VABS-3 Socialization domain scores, which were already more than 1 SD below the normative mean at baseline, decreased further, particularly in younger participants. Correlation analyses showed that poorer communication abilities were associated with increased problematic behaviors (R = -.55 for CBCL Total Problems and VABS-3 Communication scores). Mixed-effects modeling identified age as the strongest predictor of worsening behavioral outcomes. SIGNIFICANCE:We found that behavioral and social-emotional problems are inherent components of DS that present in toddlerhood and worsen throughout early childhood. This highlights the need to diagnose and manage these issues early. Targeted therapy may alleviate the wide-ranging morbidities that are intrinsic to DS, including the social-emotional and behavior problems that frequently emerge.

OBJECTIVE:Dravet syndrome is a developmental and epileptic encephalopathy characterized by drug-resistance, lifelong seizures, and significant comorbidities including intellectual and motor impairment. Receiving a diagnosis of Dravet syndrome is challenging for parents/caregivers, and little research has focused on how the diagnosis should be given. A Delphi consensus process was undertaken to determine key aspects for healthcare professionals (HCPs) to consider when communicating a Dravet syndrome diagnosis to parents/caregivers. METHODS:Following a literature search and steering committee review, 34 statements relating to the first diagnosis consultation were independent- and anonymously voted on (from 1, totally inappropriate, to 9, totally appropriate) by an international group of expert child neurologists, neuropsychiatrists, nurses, and patient advisory group (PAG) representatives. The statements were divided into five chapters: (i) communication during the first diagnosis consultation, (ii) information to be delivered during the first diagnosis consultation, (iii) points to be reiterated at the end of the first diagnosis consultation, (iv) information to be delivered at subsequent consultations, and (v) communication around genetic testing. Statements receiving ≥ 75% of the votes with a score of ≥7 and/or with a median score of ≥8 were considered consensual. RESULTS:The statements were evaluated by 44 HCPs and PAG representatives in the first round of voting; 29 statements obtained strong consensus, 3 received good consensus, and 2 did not reach consensus. The committee reformulated and resubmitted 4 statements for evaluation (42/44 voters): 3 obtained strong consensus and 1 remained not consensual. The final consensual recommendations include guidance on consultation setting, key disease aspects to convey, how to discuss genetic testing results, disease evolution, and the risk of SUDEP, among other topics. SIGNIFICANCE:It is hoped that this international Delphi consensus will facilitate a better-structured initial diagnosis consultation and offer further support for parents/caregivers at this challenging time of learning about Dravet syndrome. PLAIN LANGUAGE SUMMARY:Diagnosis of Dravet syndrome, a rare and severe form of childhood-onset epilepsy, is often challenging to give to parents. This international study developed guidance and recommendations to help healthcare professionals better structure and personalize this disclosure. By following this advice, doctors can provide more tailored support to families, improving their understanding and management of the condition.

Objectives Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that requires significant caregiver input across the lifespan. This predominantly falls on parents, who are faced with considerable challenges including physical demands, financial burdens, and sustained pressure on mental wellbeing leading to mental health difficulties. We aimed to develop a grounded theory model for the process of coping and adjustment that occurs when caring for a child who has a diagnosis of DS. Methods Using a Constructivist Grounded Theory methodology, we conducted five focus groups, each with 4-6 participants, and 24 in total. They were recruited via convenience sampling through a national Dravet syndrome patient advocacy group. Focus group dialogue was recorded, transcribed, and coded into themes to generate a theory of coping and adjustment that is grounded in the data. Results We developed a model of coping and adjustment for parents caring for a child with Dravet syndrome. The model includes contextual factors that impact on parents (loss and insufficient resource). We found a prominent theme of trauma and explored how parents responded to this trauma over time. All parents described a primary coping response reflecting the high levels of stress they had to contend with. Some parents were able to describe a secondary coping style that appeared to support healthier long-term coping and adjustment. Significance The study provides novel insight into the ways in which parents cope and adjust to caring for a child with DS, with a focus on adapting to trauma. These insights provide the foundation for the creation of targeted therapeutic interventions for parents of children with developmental and epileptic encephalopathies (DEEs), which we outline and discuss.

Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by drug-resistant seizures and multiple nonseizure comorbidities. While disease management has mainly focused on seizure control, there is growing recognition of the importance of nonseizure outcomes in treatment evaluation. This review examines evidence for treatment effects on key nonseizure domains including cognitive functioning, adaptive behavior, speech and language, neurobehavior, sleep, motor outcomes, orthopedic sequelae, nutrition/growth, and quality of life. There is limited evidence following anti-seizure medication trials suggesting improvements in executive function, particularly in preschool-aged children, though findings are inconsistent across studies. Sodium channel blockers are contraindicated, with evidence linking their use to cognitive decline and reduced quality of life. For neurobehavioral symptoms, pharmacological and nonpharmacological treatments show promise in reducing ADHD and behavioral difficulties. Sleep disturbances affect most patients, but evidence for melatonin efficacy is limited. Motor impairments are common, including delayed development, gait abnormalities, and decreased mobility and limited evidence suggests improvements with pharmacological treatment for parkinsonian symptoms. Orthopedic complications include scoliosis, while feeding difficulties may necessitate gastrostomy tube placement. Quality of life measures indicate significant impact from nonseizure symptoms, with evidence of improvement with anti-seizure medication treatment. Overall, findings are limited by small sample sizes, heterogeneous outcome measures, and over-reliance on caregiver reporting. There is a significant knowledge gap regarding disease comorbidities, and future research should investigate nonseizure outcomes alongside seizure control in interventional studies. Dravet syndrome research will benefit from the development of standardized tools validated in the DS population, and establish a core set of outcome measures, prioritized by families, clinicians and researchers to enable meaningful comparison across studies.

In randomised controlled trials, adjunctive cenobamate (CNB) has been shown to reduce seizure frequency in patients with drug-resistant focal epilepsy. Studies conducted in real-world settings provide valuable complementary data to further characterise the drug’s profile. To assess the efficacy, retention and tolerability of adjunctive cenobamate (CNB), and to identify factors that might predict these outcomes in the clinical treatment of focal epilepsies. This multicentre, retrospective cohort study included all patients who began CNB treatment between October 2020 and April 2023 at seven participating epilepsy centres. Baseline and follow-up data were collected from patients’ medical records, covering clinical characteristics and outcome data such as seizure frequency, dosing of CNB, physician-assessed Clinical Global Impression of Change, treatment-emergent adverse events (TEAEs), CNB retention and reasons for discontinuation. A total of 234 patients [mean age 40.7 ± 14 years, median 40 years, range 11–82 years; five adolescents under 18 years; 99 (42.3

This Viewpoint describes the benefits and challenges of integrating genomic information with disease-modifying therapies for epilepsy.

DNA methylation signatures ("episignatures") can be used as biomarkers of genetic aberrations, clinical phenotypes, and environmental exposures in rare diseases. Episignatures are utilized in molecular diagnostics and can clarify variants of uncertain significance. A growing number of disease genes, including epilepsy genes, exhibit robust and reproducible episignatures. However, whether SCN1A, the most prominent epilepsy gene, has one or more episignatures has not yet been determined. We generated genome-wide DNA methylation data and performed episignature analysis on 64 individuals with Dravet syndrome due to pathogenic loss-of-function (LOF) variants in SCN1A and seven individuals with early infantile SCN1A developmental and epileptic encephalopathy due to pathogenic gain-of-function (GOF) variants in SCN1A, relative to a large reference database of controls and rare disease episignature-positive cohorts. We analyzed all samples with LOF variants together and performed separate analyses for missense, nonsense, and GOF variant cohorts. A reproducible blood-derived episignature was not evident in any of the cohorts using current analytical approaches and reference data.

OBJECTIVE:Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug-resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood. METHODS:The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A+ DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI-IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS-3), Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P), and Pediatric Evaluation of Disability Inventory (PEDI). RESULTS:Fifty-eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age-appropriate milestones. Mean BSID-III Cognitive raw scores increased minimally, with age-equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: -11.0, 95% confidence interval [CI]: -15.3 to -6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF-P Global Executive Composite T-scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS-3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: -9.0, 95% CI: -11.9 to -6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. SIGNIFICANCE:Infants and young children with SCN1A+ DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.