Search Results (178)

Neonatal seizures represent the most common neurological emergency in the neonatal period and arise within a uniquely immature and highly dynamic brain. Their recognition is challenging due to frequent electroclinical dissociation, with many seizures remaining purely electrographic and therefore detectable only through continuous electroencephalogram (cEEG) monitoring. This narrative review provides an integrated and updated overview of neonatal seizures, bridging developmental neurobiology, diagnostic challenges, etiological classification, and therapeutic strategies. The immature brain is characterized by an imbalance between excitation and inhibition, transient network architectures, and activity-dependent developmental processes, all of which contribute to the distinct electroclinical features of neonatal seizures. cEEG remains essential for accurate diagnosis and quantification of seizure burden, which may influence outcome. Etiology represents the primary determinant of prognosis, with hypoxic–ischemic encephalopathy (HIE), stroke, and genetic disorders among the most frequent causes. Advances in genetic testing have improved diagnostic precision and enabled targeted therapies in selected cases, supporting a precision medicine approach. Several key findings emerge from the current evidence base: (i) the neonatal brain is a developmentally constrained system in which excitation–inhibition imbalance, transient circuits and immature long-range connectivity shape an electroclinically distinct seizure phenotype; (ii) cEEG is the gold standard for detection and quantification of seizure burden, since the majority of neonatal seizures are electrographic-only and bedside clinical recognition systematically underestimates true seizure burden; (iii) etiology—chiefly HIE, stroke, and genetic causes—remains the strongest determinant of outcome, while seizure burden acts as an independent and potentially modifiable prognostic modifier; (iv) phenobarbital retains an evidence-based advantage in acute electrographic seizure control, whereas levetiracetam offers a favorable safety profile in the absence of robust long-term human neurotoxicity data; (v) rapid genomic diagnostics, artificial intelligence-assisted EEG analysis and multimodal neuromonitoring are converging toward a precision-neonatology framework, but their translation into routine practice requires validation, standardization, and equitable access. Future neonatal seizure care should extend beyond seizure control to the preservation and optimization of neurodevelopmental outcomes. Full article

Aspartate–glutamate carrier 1 (AGC1) deficiency is a rare neurometabolic disorder caused by biallelic pathogenic variants in SLC25A12. Clinically, it is characterized by early-onset developmental and epileptic encephalopathy, often associated with hypomyelination and reduced brain N-acetylaspartate. AGC1 loss reduces malate–aspartate shuttle flux, limiting cytosolic NAD⁺ regeneration and impairing neuronal redox coupling, ATP supply, and aspartate-dependent biosynthesis during brain development. We integrate human genetics with mechanistic evidence from mammalian, Drosophila melanogaster, and Saccharomyces cerevisiae models to describe conserved transport principles and species-specific regulation underlying selective central nervous system vulnerability. We review the management of AGC1 deficiency, focusing on ketogenic therapy. Published reports show reproducible seizure reduction and, in some patients, improved myelination and N-acetylaspartate. However, these responses are heterogeneous and appear to depend on the timing, duration, and stability of ketosis. Preclinical evidence suggests that β-hydroxybutyrate may contribute to metabolic support in AGC1 deficiency. Prospective studies should test disease modification using standardized endpoints plus MRI/¹H-MRS and ketosis measures. Full article

De novo variants in CACNA1E, the gene encoding the Cav2.3 voltage-gated calcium channel, are often associated with severe neurodevelopmental disorders, including developmental and epileptic encephalopathy. All reported variants up to date have exhibited gain-of-function effects on their biophysical properties. Here, we functionally characterize three pathogenic CACNA1E variants: H151L, M163T, and R1182C, using electrophysiology and structural modeling. M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation. Our findings provide the first mechanistic evidence linking loss-of-function Cav2.3 pathogenic variants to variable neurological phenotypes, expanding the clinical spectrum of CACNA1E channelopathies. Full article

Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a “rare-but-many” landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy–lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies. Full article

Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficient Disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early-onset refractory epilepsy, severe neurodevelopmental impairment, and lifelong disability. Although more than thirty anti-seizure medications are available, most CDD patients remain pharmaco-resistant. Gene-based therapies are emerging, but therapeutic development is hindered by marked clinical heterogeneity, small patient populations, and the lack of robust, translatable brain-based biomarkers for clinical trials. Genetically engineered Cdkl5 mouse models recapitulate many cognitive, behavioral, and molecular features of CDD, yet their utility is limited by the absence of overt seizures, precluding seizure-based outcome measures. Here, we establish high-definition brain network (HDBN) biomarkers using advanced diffusion MRI tractography combined with graph-theoretical analysis to quantify whole-brain network organization in Cdkl5 knockout mice. Diffusion MRI enables non-invasive mapping of axonal connectivity by leveraging anisotropic water diffusion, while high-angular-resolution acquisition overcomes key limitations of conventional diffusion tensor imaging in regions with complex fiber architecture. We demonstrate that Cdkl5 knockout mice exhibit reproducible and region-specific disruptions in brain network organization, prominently affecting the somatosensory and somatomotor cortex, hippocampus, hypothalamus, amygdala, and superior colliculus—regions implicated in cognition, learning and memory, homeostasis, anxiety, and visual–motor function. In contrast, networks within the entorhinal cortex remain largely preserved. These findings identify HDBN metrics as sensitive, non-invasive biomarkers that capture clinically relevant circuit-level abnormalities in CDD. Because diffusion MRI–based network analyses are directly translatable across species, HDBN biomarkers provide a unified framework for therapeutic evaluation in mouse models, large animals, and human clinical trials, enabling longitudinal monitoring of disease progression and treatment response. Full article

The WW domain-containing oxidoreductase (WWOX) gene, well-known as a tumor suppressor, also has a crucial role as a transcription factor in the developing brain. The bi-allelic loss of the WWOX gene causes a condition characterized by drug-resistant epilepsy, developmental delay, and neurological impairments, often resulting in mortality within the first year of life, known as WWOX-related epileptic encephalopathy (WOREE) syndrome (MIM: 616211). Whole Exome Sequencing (WES) analysis was performed on a female patient who died within three months of birth and was diagnosed with microcephaly, severe early-onset refractory seizures, and drug-resistant epileptic encephalopathy. WES revealed a 38 kb CNV deletion spanning WWOX exons 6–7, and a known frameshift variant in exon 8, impairing a highly clinically significant region of the encoded protein. Clinical and genetic features of reported WOREE patients with WWOX gene deletions similar to our patient were analyzed. Our case highlights the clinical heterogeneity of WWOX variants in WOREE syndrome and expands the spectrum of reported compound heterozygous deletions. Further research needs to elucidate WWOX pathophysiology and improve diagnostic and therapeutic strategies. Full article

Background/Objectives: Early-onset epilepsy is associated with a high risk of developing drug-resistant epilepsy (DRE), often manifesting as developmental and epileptic encephalopathies (DEEs). This study aimed to characterize the incidence, syndromes, comorbidities, and etiology of early-onset DRE in Estonia. Methods: This study is a continuation of our earlier nationwide, population-based investigation and included all children with early-onset epilepsy (seizure onset before two years) who developed drug resistance in Estonia between 2013 and 2017 (n = 37). Cases were identified at the country’s only two pediatric neurology departments, ensuring nationwide coverage. Clinical data, electroencephalography, neuroimaging, genetic investigations (chromosomal microarray, single-gene tests, gene panels, exome/genome sequencing), and etiology were analyzed overall and by epilepsy type or syndrome. Results: A total of 37 children with early-onset DRE were included. The incidence of early-onset DRE was 26.5 per 100,000 person-years, peaking in the first year of life (36.1). Drug resistance developed in 43% within six months and 65% within one year. DEEs accounted for 76% of cases, most commonly infantile epileptic spasms syndrome (IESS/West syndrome, 35%). Structural abnormalities were observed in 49% of cases (50% of DEEs), most commonly congenital brain malformations (22%). Pathogenic genetic findings were identified in 41% overall (43% of DEEs). The etiology was established in 78% of children with DRE. Among DEEs, it was found in all Dravet syndrome patients (100%) and 62% of those with IESS/West syndrome. Global developmental delay/intellectual disability occurred in 86%, and motor impairment in 46%. Conclusions: Early-onset DRE, often presenting as DEE, has high incidence, progresses rapidly to drug resistance, and causes substantial comorbidities. Full article

Background/Objectives: CDKL5 deficiency disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early onset refractory epilepsy and severe neurodevelopmental impairment with autistic features. Despite advances in genetic diagnosis, objective biomarkers reflecting disease mechanisms remain limited. Extracellular vesicles (EVs) circulating in the blood may contain disease-related proteins derived from the central nervous system. This study aimed to characterize the plasma EV proteome in CDD in a hypothesis-generating exploratory framework and identify the candidate molecular pathways associated with this disorder. Methods: Plasma samples from seven patients with genetically confirmed CDD and seven neurotypical developmental controls were analyzed. Extracellular vesicle-containing preparations (EVs-cp) were isolated via immunoprecipitation using antibodies against CD9, CD63, and CD81. Proteomic profiling was performed using data-independent mass spectrometry. Differentially expressed proteins were identified using Welch’s t-test with a false discovery rate correction. Functional enrichment, protein interaction network, and correlation analyses were performed using CDKL5 Clinical Severity Assessment (CCSA) scores. Results: In total, 5617 proteins were identified, of which 3510 were used for quantitative analysis. Compared to the controls, 2108 proteins were upregulated and 158 were downregulated in the CDD samples. Enrichment analysis revealed alterations in vesicle-mediated transport, cytoskeletal organization, and immune-related pathways. Several proteins were also correlated with clinical severity scores. Conclusions: Plasma EV proteomics revealed molecular alterations associated with CDD and provided a potential approach for biomarker discovery and mechanistic investigation. Full article

Epilepsy is a progressive network disorder in which recurrent seizures drive maladaptive neurodevelopmental remodeling, cognitive decline, and pharmacoresistance, particularly in developmental epileptic encephalopathies. Cannabidiol (CBD) has emerged as an evidence-based adjunctive therapy for selected childhood-onset epilepsies; however, its broader clinical utility remains limited by heterogeneous responsiveness, restricted indications, and an incomplete understanding of developmental stage–specific efficacy and safety. Here, we synthesize molecular, preclinical and clinical evidence supporting the pleiotropic antiseizure and neuroprotective actions of CBD, including modulation of endocannabinoid-related G protein–coupled receptors, adenosine signaling, transient receptor potential channels, GABAergic maturation, and neuroinflammatory cascades. We highlight critical neurodevelopmental windows during which timely CBD intervention may exert disease-modifying effects by preventing pathological consolidation of hyperexcitable networks. Furthermore, we position human brain organoids as transformative translational platforms that recapitulate early human cortical development and epileptic network dynamics, enabling functional stratification of CBD-responsive phenotypes, developmental safety profiling, and precision therapeutic discovery within human-relevant neural circuits. Collectively, organoid-guided frameworks provide a mechanistic foundation for personalized, developmentally informed CBD therapy and advance precision medicine strategies aimed at modifying epileptogenic trajectories rather than solely suppressing seizures. Full article

Background: Hypoxic–ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term neurodevelopmental impairment despite advances in perinatal care and the widespread use of therapeutic hypothermia. Reliable early prognostic markers are essential for risk stratification and long-term follow-up planning. This study aimed to evaluate long-term neurodevelopmental outcomes and associated prognostic factors in neonates with HIE treated in the era of therapeutic hypothermia. Methods: This retrospective cohort study was conducted in a tertiary neonatal intensive care unit between January 2020 and June 2024. Neonates with gestational age ≥ 35 weeks diagnosed with HIE were included. Clinical characteristics, laboratory parameters, neurophysiological findings, neuroimaging results, and indicators of multiorgan dysfunction were recorded. Long-term neurodevelopmental outcomes were assessed at 18 to 24 months of age. The primary outcome was death or severe neurodevelopmental impairment. Multivariable logistic regression analysis was performed to identify independent predictors of adverse outcomes. Results: A total of 99 neonates were included. Therapeutic hypothermia was administered to 86 (86.9%) infants. Severe neurodevelopmental impairment or death occurred in 18 (18.2%) patients. Cerebral palsy was diagnosed in 19 (20.9%) survivors, developmental delay in 12 (13.2%), epilepsy in 16 (17.6%), and feeding difficulties in 9 (9.9%). In multivariable analysis, higher lactate levels (adjusted OR = 1.239, 95% CI = 1.052–1.458), lower Apgar score at 5 min (adjusted OR = 0.570, 95% CI = 0.344–0.944), and renal dysfunction (adjusted OR = 7.947, 95% CI = 2.027–31.164) were independently associated with severe neurodevelopmental impairment or death. Multiorgan dysfunction and abnormal neurophysiological and neuroimaging findings were significantly associated with adverse outcomes. Conclusions: Early biochemical markers, neurological assessments, neurophysiological recordings, neuroimaging patterns, and systemic organ dysfunction are closely associated with long-term neurodevelopmental outcomes in neonates with HIE. A multidimensional approach to early prognostic evaluation may improve risk stratification and guide targeted follow-up and intervention strategies. Full article

CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early disruptions of synaptic maturation and network stability, leading to persistent motor, cognitive, and behavioral impairments. Given the role of the endocannabinoid system in synaptic development, neuroinflammation, and neuronal resilience, we investigated whether the sustained enhancement of endogenous 2-arachidonoylglycerol (2-AG) signaling via monoacylglycerol lipase (MAGL) inhibition could mitigate key pathological features in adult Cdkl5 knockout (KO) mice. Using an intermittent 6-week treatment, the MAGL inhibitor JZL184 robustly increased plasma 2-AG levels, reduced MAGL protein levels, and activated CB1-AKT signaling without evidence of receptor desensitization. Despite this clear pharmacodynamic efficacy, behavioral effects were domain-specific: neither dose ameliorated core behavioral deficits, although the higher dose selectively reduced stereotypic jumping and modestly improved cue-dependent associative memory. At the cellular level, JZL184 induced biologically meaningful effects, partially restoring dendritic spine maturation in the primary somatosensory cortex and increasing neuronal survival in the vulnerable CA1 hippocampal region. In contrast, microglial responses were dose-dependent and divergent, with the lower dose exerting anti-inflammatory effects, while the higher dose increased cortical microglial density and Allograft Inflammatory Factor-1 (AIF-1) expression, suggesting engagement of compensatory or off-target mechanisms. Overall, these findings show that MAGL inhibition activates neuroprotective pathways and ameliorates select structural deficits in adult Cdkl5 KO mice, but is insufficient to produce broad behavioral recovery, highlighting the domain-specific effects of selective 2-AG enhancement via MAGL inhibition and the need for developmentally informed or multimodal therapeutic strategies in CDD. Full article

Introduction: SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is an epileptic encephalopathy linked to mutations in the SLC6A1 gene and is characterized by early-onset seizures and developmental delays. Despite the growing recognition of SLC6A1 as a major cause of early-onset epilepsy, the electrophysiological changes associated with the disorder remain inadequately characterized. This study aims to identify electrophysiological biomarkers of SLC6A1-NDD by characterizing EEG delta power using automated tools, EEGLAB (v2023.1) and Persyst 13, exploring age- and state-related effects. Methods: We analyzed EEG recordings from 20 patients with SLC6A1-NDD and 20 neurotypical age- and sex-matched controls using EEGLAB and Persyst, quantifying delta power and related metrics. The Wilcoxon signed-rank method tested for differences between patients and controls, area under the curve (AUC) values evaluated patient classifier models, and Pearson’s correlation assessed concordance between EEGLAB and Persyst. Results: Patients with SLC6A1-NDD exhibited significantly elevated delta power (19.4 ± 4.1) compared to controls (14.2 ± 3.0; p < 0.001). The mean delta power showed an age-dependent increasing trend in patients (b = 0.5), contrasting with a decline in controls (b = −1.0; p < 0.001). In Persyst, the frequency of delta activity above an optimized threshold best differentiated patients from controls in wake epochs (AUC = 0.93). Concordance between EEGLAB and Persyst was one-to-one but with moderate variability (R² = 0.644; p < 0.001). Conclusions: Elevated delta power is a notable feature of SLC6A1-NDD. Cross-platform comparison demonstrates the feasibility of quantitative EEG analysis, while imperfect concordance highlights the need for pipeline standardization. Future work should validate these findings in larger cohorts and, as suitable reference data emerge, benchmark delta power metrics against age-matched children with other developmental and epileptic encephalopathies. Full article

Developmental and epileptic encephalopathies (DEEs) represent the most severe group of epilepsies, characterized by drug-resistant seizures, frequent occurrence of epileptiform activity, developmental delay or cognitive impairment. Recent insights have reframed DEEs from static, genetically determined conditions to dynamic disorders with complex and evolving pathophysiology. Several recent studies suggest a link between epilepsy and neurodegeneration, with increased neuronal excitability preceding seizures in conditions characterized by abnormal protein aggregation. Neurodegeneration, defined as the selective and progressive loss of neuronal cells leading to cognitive and functional decline, underlies many progressive neuronal diseases. Although neurodegeneration biomarkers are widely recognized as markers of disease progression in adults, their role in children is still poorly defined and at times controversial. This narrative review aims to summarize current knowledge on the relationship between epilepsy and neurodegeneration, with a focus on potential biomarkers and their implications for disease mechanisms and progression. Full article

Background: Complex neurodevelopmental disorders frequently reflect multiple neurologic symptoms which have shared molecular and network level mechanisms. Advances in genomic medicine have redefined these conditions as overlapping manifestations of brain circuit dysfunction with significant variability. This review examines the intersection of genomics, epilepsy, and neurodevelopment in complex neurodevelopmental disorders, emphasizing Dup15q syndrome as a model for understanding phenotypic variability. Methods: Authors conducted a clinical (non-systematic) review of the literature based on their experience with three patients with Dup15q who responded dramatically to neurostimulation. We synthesized current literature on genomic mechanisms underlying complex neurodevelopmental disorders focusing on Dup15q syndrome and its subtypes—int15, idic15, and mosaic idic15. We integrated clinical, electrophysiologic, and molecular data to illustrate the spectrum of epilepsy phenotypes and their mechanistic underpinnings. Results: Dup15q syndrome demonstrates marked heterogeneity in epilepsy severity and seizure semiology, reflecting variable gene dosing effects, maternal imprinting of UBE3A, and altered GABAergic signaling. While idic15 is more strongly associated with refractory epilepsy and SUDEP, both idic15 and int15 subtypes show overlapping developmental and behavioral phenotypes. There is a well-known differential response to anti-seizure medications and emerging evidence for neurostimulation and precision medicine. Conclusion: Dup15q syndrome exemplifies the convergence of genomic, neurophysiologic, and developmental pathways in epilepsy. As genomic discovery expands, precision therapies will increasingly rely on collaborative research networks. Understanding the genomic architecture of Dup15q syndrome may inform personalized strategies for epilepsy treatment and prevention. Full article

Lennox–Gastaut syndrome (LGS) is a rare and severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, mandatory tonic seizures, cognitive and behavioral impairment, and distinctive electroencephalographic features, including slow spike–wave discharges and generalized paroxysmal fast activity. Despite decades of therapeutic advances, LGS remains associated with profound lifelong disability and the absence of a single disease-defining molecular mechanism. Recent advances in genetics, neurophysiology, and network neuroscience have reframed LGS as a convergent network encephalopathy, in which diverse genetic, structural, metabolic, immune, and acquired insults funnel into shared molecular hubs, leading to thalamocortical network dysfunction. This framework helps explain the limited efficacy of purely syndrome-based treatments. This review synthesizes current evidence on electroclinical phenotyping, molecular and network pathogenesis, and contemporary diagnostic workflows and proposes a molecule-to-precision-therapy framework for LGS. We critically appraise pharmacologic, dietary, surgical, and neuromodulatory therapies, emphasizing drop seizures as a major driver of morbidity. Among available treatments, cannabidiol shows the most consistent and clinically meaningful efficacy for drop seizures, with benefits extending beyond seizure counts to seizure-free days and caregiver-relevant outcomes. Finally, we highlight key gaps and future directions, including etiology-stratified trials, network-guided interventions, and outcome measures that capture long-term developmental and quality-of-life impacts. Full article