Aug 2026· Annals of Clinical and Translational Neurology· 0 citations· 27 references
Medicine
TL;DR
It is revealed that fever‐related seizure reduction is a distinctive and prevalent genotype–phenotype for CDD, thereby providing evidence for further fundamental research into the underlying mechanisms and offering potential clinical implications for seizure control in CDD.
Abstract
ABSTRACT Objective CDKL5 deficiency disorder (CDD) is a rare, severe developmental and epileptic encephalopathy. There is a pressing need to develop effective and sustainable therapeutic strategies. We aimed to investigate the causal association between febrile episodes and epileptic seizures for therapeutic implications in CDD patients. Methods The study was a nationwide, cross‐sectional survey on CDD patients in China (ClinicalTrials.gov, NCT06663163). Detailed phenotypic and genotypic data were collected through an online questionnaire with uploaded original medical records, genetic testing results, and peri‐fever seizure diaries. The primary outcome was changes in epileptic seizure frequency during and post‐fever phases compared to a 1‐month pre‐fever phase based on seizure diaries. Results Between October 2024 and December 2024, we received 131 questionnaires. Forty‐seven questionnaires were removed after excluding duplicates and missing data. Ultimately, 84 eligible participants with complete uploads were included, from 26 of 34 (76.5%) province‐level regions in China. Among these, 47 (56.0%) patients had significant decreased seizure frequency only during febrile episodes, and 27 (32.1%) patients with daily seizures achieved at least a seizure‐free day. Notably, 20 patients (23.8%) exhibited post‐fever seizure reduction: 12 (25.5%) for 3 days to 1 week, and 6 (12.8%) for more than 2 weeks (maximum > 40 days). The effect was independent of patients' clinical and genetic characteristics. Interpretation Our findings, for the first time, revealed that fever‐related seizure reduction is a distinctive and prevalent genotype–phenotype for CDD, thereby providing evidence for further fundamental research into the underlying mechanisms and offering potential clinical implications for seizure control in CDD.
Background and Objectives KCNT1-related epilepsy is an ultra-rare pediatric-onset developmental and epileptic encephalopathy with a broad clinical phenotype ranging from, most commonly, severe infantile-onset epilepsy and global developmental delay to, less commonly, milder phenotypes including sleep-related seizures, autism spectrum disorder, and learning disability. We initiated the first-ever prospective natural history study to comprehensively clinically phenotype individuals affected by this disorder. Methods The primary aim of this study was to characterize seizures in individuals with KCNT1-related epilepsy. Secondary and exploratory aims included characterization of the full spectrum of disease symptoms, understanding caregiver burden, and collection of blood and urine samples for biomarker exploration. All study activities were conducted remotely (e.g., home-based assessments, telehealth visits). Results Thirty-five participants (n = 20 male, 15 female) were enrolled in this study. The average age at the baseline visit was 76.0 months (s.d. = 75.5). This article presents the study design and methods and several challenges that arose in its implementation and discusses various solutions implemented in this medically complex population. Discussion Future work will apply the lessons from this study in the planning and design of clinical trials for KCNT1-related epilepsy and possibly other developmental and epileptic encephalopathies.
Heather R. Adams, Viet Nguyen, L. Seltzer et al.· Neurology: Genetics· 0 citations
Five novel HCN1 variants are reported here and trends in ASM efficacy are similar to what has been observed in Dravet syndrome, another EIEE, raising questions about potential common pathogenic mechanisms at a cellular level.
Marium N Khan, N. Poolos· Epilepsia Open· 0 citations
“hemiconvulsion-hemiplegia-epilepsy syndrome” is identified as a distinct feature and potential prognostic indicator for middle domain variants in DNM1L variants, which are predominantly missense, with the middle domain as a hotspot.
Han Xu, Chaolong Xu, Ying Zou et al.· Frontiers in Neurology· 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
A comprehensive understanding of the clinical spectrum and genotype-phenotype correlation in KCNT1-related disorders is offered and the need to develop multisource data methodologies and registries to reduce follow-up loss in real-world data collections based on health records is highlighted.
Mathilde Gras, Gaëlle Quentin-Romand, N. Chemaly et al.· Brain Communications· 0 citations
The observed burden of DRE and polytherapy supports the potential value of integrating therapeutic profiling, neuroimaging, and genomic testing in the etiological evaluation of patients with epilepsy and additional neurological features.
I.A. Doszhanov, Sandugash Rustemova, Nigara Yerkhojayeva et al.· International Journal of Tra...· 0 citations
