The relationship between electroclinical features and etiology, as well as the genotype-phenotype characterizations and prognosis with genetically determined DEEs, are defined and several novel variants in disease-associated genes are described.
Abstract
Objective
Developmental and epileptic encephalopathies (DEEs) are characterized by refractory seizures and frequently recurring epileptic activity with neurodevelopmental delay or regression that usually begin in early life. We aimed to define the relationship between electroclinical features and etiology, as well as the genotype-phenotype characterizations and prognosis with genetically determined DEEs.
Methods
We retrospectively evaluated patients with DEEs who were referred to the Division of Pediatric Neurology at our university hospital between 2017 and 2021 and followed for at least 24 months. Demographic characteristics, etiologies, genetic findings, and electroclinical phenotypes were analyzed in 136 children with DEEs.
Results
In our study, 50.7% of the patients were female. Age at presentation ranged from 1 to 126 months and the mean age at seizure onset was 9.4 months. Etiology was genetic in 41 patients (30.1%), structural in 32 patients (23.5%), and metabolic in 17 patients (12.5%). Among patients with a genetic etiology, 32 were genetically solved, including 28 with pathogenic or likely pathogenic single-gene variants and 4 with pathogenic copy number variants or chromosomal rearrangements. Eight additional patients had phenotype-concordant variants of uncertain significance, and one patient had a clinical-only genetic diagnosis. SCN1A was the most frequently affected gene. Electroclinical phenotypes in genetic DEEs were as follows: EIDEE in 11 patients, Dravet syndrome in 10, IESS in 6, EMAS in 2, LGS in 2, and unclassified in 10 patients.
Significance
We characterized DEEs with genetic etiology in our cohort and described their associated electroclinical phenotypes, including several novel variants in disease-associated genes. Understanding the diverse underlying etiologies of DEEs in children, along with their genotypic and phenotypic characteristics, is crucial for early diagnosis and treatment and the development of targeted management strategies.
Early-onset epilepsy in infancy exhibits heterogeneous features and the ILAE framework facilitates a systematic diagnostic approach and supports clinical management in pediatric patients.
OBJECTIVE
This study was undertaken to assess cenobamate (CNB) effectiveness, tolerability, and dosing in pediatric developmental and epileptic encephalopathies (DEEs), testing prespecified hypotheses on response by syndrome, etiology, electroencephalographic pattern, seizure type, CNB dose (mg/kg/day), and concomitant medication.
METHODS
A retrospective multicenter cohort of children (≤18 years old) with DEEs were treated with CNB at 17 Spanish hospitals. Primary outcomes were retention, response (≥50% reduction), and seizure freedom at 3, 6, and 12 months. Mixed-effects logistic and ordinal models were adjusted for age, syndrome, etiology, seizure type, and concomitant medication.
RESULTS
Among 152 children (median age = 12 years), 27.6% had Lennox-Gastaut syndrome (LGS) and 58.6% unspecified DEE, with a median of 9 prior antiseizure medications. Retention was 88%, 90%, and 93% and responder rates 64%, 73%, and 79% at 3, 6, and 12 months; seizure freedom was 8%, 12%, and 18% (evaluable n = 152, 105, and 57 at 3, 6, and 12 months, respectively). LGS and other DEEs reached identical 12-month responder rates (both 79%), whereas Dravet syndrome showed limited sustained benefit. By etiology, structural cases had the highest 12-month responder rate (93% vs. 68% in nonstructural, p = .04), but no etiology was independently associated with response. By seizure type, responder rates were highest for tonic (81%) and bilateral tonic-clonic (76%) and lowest for absences (54%, adjusted odds ratio [OR] = .43, p = .032). Treatment-emergent seizure worsening occurred in 10.5%. Sodium channel blockers were the main risk factor for adverse events (OR = 2.10); 10.5% discontinued CNB due to adverse events.
SIGNIFICANCE
CNB was associated with sustained effectiveness and acceptable tolerability across pediatric DEEs. Slow weight-based titration and proactive simplification of sodium channel blockers and clobazam may optimize benefit-risk.
Ángel Aledo-Serrano, Adrián Valls-Carbó, E. González-Alguacil et al.· Epilepsia· 0 citations
PURPOSE
WWOX-related developmental and epileptic encephalopathy (WOREE) is a rare autosomal recessive disorder caused by biallelic pathogenic WWOX variants, characterized by very early-onset epilepsy, profound developmental delay, and progressive brain abnormalities. Detailed electroclinical descriptions remain limited.
METHODS
We conducted a retrospective study of seven patients with pathogenic/likely pathogenic WWOX variants. Clinical features, seizure evolution, EEG findings, brain MRI, and genetic data were reviewed. Epilepsy syndromes were classified according to International League against Epilepsy (ILAE) criteria. Variants were identified through next-generation sequencing and interpreted following American College of Medical Genetics and Genomics (ACMG) guidelines.
RESULTS
Median seizure onset was 3 months (range 2-6). Five patients presented with focal seizures evolving to infantile epileptic spasms syndrome (IESS), while two had IESS at onset. Epilepsy was drug-resistant in all. Developmental delay was evident from birth with generalized hypotonia, acquired microcephaly, and impaired visual attention. Four patients had dysmorphic features. During the IESS period, EEG showed hypsarrhythmia in six patients and a severely disorganized encephalopathic background that did not strictly fulfill the criteria for hypsarrhythmia in one. Brain MRI revealed abnormalities in all patients, including frontotemporal atrophy and corpus callosum hypoplasia; delayed myelination was observed in one case. Eight pathogenic/likely pathogenic WWOX variants were found; including one novel variant (NM_016373.4:c.571C>T, p.(Gln191*)). The recurrent splice-site variant NM_016373.4:c.107+1G>A was identified in five patients, suggesting a possible regional founder effect.
CONCLUSION
WOREE shows a recognizable electroclinical and neuroimaging profile with early drug-resistant epilepsy and profound developmental delay. Recognition of this pattern may facilitate early diagnosis and targeted genetic testing, particularly in populations with recurrent variants.
Jose Guevara, M. Touzon, Sara Negrete et al.· Seizure· 0 citations
PURPOSE
Rasmussen encephalitis (RE) is a rare progressive inflammatory disorder characterized by drug-resistant focal epilepsy and unilateral cerebral atrophy. This study aimed to evaluate the longitudinal electroclinical, neuroradiological, treatment, and surgical characteristics of pediatric and adult patients with RE followed at a tertiary referral center.
METHODS
Fourteen patients (10 females) with a median follow-up of 75.5 months were retrospectively reviewed. Clinical characteristics, serial electroencephalography (EEG), brain magnetic resonance imaging (MRI), immunotherapy regimens, surgical interventions, and seizure outcomes were analyzed.
RESULTS
Median age at symptom onset was 102 months. Focal motor seizures were the initial presenting symptom in 86% of patients, and epilepsia partialis continua developed in 57%. Serial EEG demonstrated progression from focal epileptiform abnormalities to regional and hemispheric slowing confined to the affected hemisphere. Left-hemispheric involvement was observed in 71% of patients in this relatively older cohort. Initial MRI frequently demonstrated cortico-subcortical T2-weighted and fluid-attenuated inversion recovery (FLAIR) hyperintensities preceding progressive cortical atrophy. Serial MRI revealed heterogeneous radiological evolution, including diffuse hemispheric and limited regional cortical atrophy patterns. Despite immunotherapy, most patients showed progressive disease and refractory seizures. Hemispherectomy resulted in seizure freedom in two of three operated patients.
CONCLUSION
RE demonstrated heterogeneous electroclinical and neuroradiological evolution across pediatric and adult patients. The coexistence of an older age profile and a predominance of left hemisphere involvement may suggest age-related phenotypic variability. Early MRI abnormalities may precede overt hemispheric atrophy, highlighting the importance of longitudinal evaluation for timely diagnosis. Although immunotherapy may provide temporary stabilization, surgical treatment appears to provide the most favorable seizure outcomes in selected patients.
Ülkühan Öztoprak, C. Günbey, Rahşan Göçmen et al.· Brain & development (Tokyo....· 0 citations
OBJECTIVE
Adrenocorticotropic hormone (ACTH) is an effective treatment for infantile epileptic spasms syndrome (IESS); however, its mechanism of action remains incompletely understood. This study aimed to evaluate ACTH treatment response at the level of protein-protein interactions (PPIs) in patients with confirmed and presumed monogenic developmental and epileptic encephalopathies (DEEs).
METHODS
Medical records of patients with DEEs followed at our center between 2017 and 2025 were retrospectively reviewed. Patients receiving ACTH therapy who harbored pathogenic, likely pathogenic, or variants of uncertain significance (VUS) were included in the study, whereas those with chromosomal abnormalities and insufficient clinical or follow-up data were excluded. Clinical and electroencephalographic (EEG) responses to ACTH therapy were evaluated at the 2-week (day 14) and 3-month follow-up visits. Maintenance of a ≥50% reduction in seizure frequency at 3-month follow-up defined responders. Gene Ontology and PPI network analyses were performed to investigate relationships between genotype and treatment response.
RESULTS
Among the 245 patients with DEEs, 69 had a confirmed genetic etiology, of whom 10 met the inclusion criteria. At 2-week follow-up, 5 of 10 patients (SCN2A, ELOVL4, CACNA1E, TRRAP) achieved seizure freedom, while 3 (PIGT, SCN1A, ZNF526) showed ≥50% reduction. At month 3, 66.6% (6/9) of patients were classified as responders. At 1 year, patients with SCN2A and PIGT variants showed sustained ≥50% seizure reduction, normalization of background EEG activity, and resolution of epileptiform discharges. PPI analysis revealed network interactions between CALM-SCN2A/CACNA1E and PRKAC-SCN1A, whereas the TRRAP-ATF2 interaction showed low confidence, and no reliable interaction was identified for PIGT.
SIGNIFICANCE
These findings suggest that ACTH may be associated with sustained electroclinical improvement in selected genetically defined DEEs. The identified network-level interactions between ion channel-related genes and intracellular signaling pathways provide a potential molecular framework for understanding variability in treatment response.
Çisem Duman Kayar, Sinan Akbaş, Fulya Kürekçi et al.· Epileptic disorders· 0 citations
Background and Objectives Enzyme replacement therapy has not only significantly improved motor outcome and survival in patients with classic infantile Pompe disease, but also revealed previously unrecognized central nervous system (CNS) involvement. In this international study, involving patients from the Netherlands, Italy, Argentina, Germany, the United Kingdom, and Taiwan, we investigated whether epilepsy should be considered part of the CNS phenotype. Methods We included patients with classic infantile Pompe disease, defined by the presence of hypertrophic cardiomyopathy, symptom onset < 6 months of age, complete acid α-glucosidase (GAA) deficiency, and/or 2 severe variants in the GAA gene, who developed epilepsy. Data on epilepsy characteristics, electroencephalogram (EEG), cognitive testing, serum neurofilament light chain (NfL), and brain magnetic resonance imaging (MRI) were retrospectively collected. Results Seventeen patients from 10 centers were identified. The median follow-up duration was 13.7 years (range 3.3–19). Seven patients had deceased at the time of analysis. The median age at first seizure was 11.5 years (range 2.5–17.5). Seizure semiology was variable: six patients experienced generalized tonic-clonic seizures and 3 focal seizures with impaired consciousness only; 6 had multiple seizure types, and 7 experienced seizures during fever or infection. Seizure frequency varied considerably (in 9 occasionally, 5 monthly, 2 weekly, 1 daily). The most common EEG findings were a slowed background activity and focal epileptiform discharges, not substantially activated by sleep. Levetiracetam was most frequently used as antiseizure medication. Overall, 70% of patients became seizure-free. Serum NfL was elevated in all 6 patients in whom it was measured, and 8 of 10 patients had an intelligence quotient ≤66 at onset of epilepsy. Although brain MRI was not always performed at the age of first seizure, 14 of 15 patients showed white matter abnormalities, which were extensive in 11 of 14 (score ≥7/12). Brain atrophy was present in 9 cases and calcifications in 4. Discussion Our findings suggest a potential increased frequency of seizures in classic infantile Pompe disease in comparison with unaffected children, occurring predominantly after the age of 7, and that epilepsy is part of the CNS phenotype. The risk of seizures should be evaluated during follow-up in long-term survivors with classic infantile Pompe disease.
M. C. Faraguna, Alexander Broomfield, S. Gasperini et al.· Neurology: Genetics· 0 citations
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