OBJECTIVE
Fever can trigger seizures in several early-onset epilepsies. SCN1A-related epilepsies, including Dravet Syndrome, are the best characterised conditions in this spectrum, but a growing number of genes implicated in fever-sensitive epilepsies have emerged. We assessed the genetic heterogeneity of individuals who underwent testing because of seizures or epilepsy with fever sensitivity. In particular, we investigated the occurrence of ATP6V0C pathogenic variants and delineated its associated electro clinical features.
METHODS
We retrospectively reviewed individuals tested with epilepsy-targeted Next Generation Sequencing (NGS) panels and/or Whole Exome Sequencing (WES) between 2022 and 2025, selecting those with documented fever sensitivity (defined as seizure occurrence or exacerbation temporally linked to febrile episodes in subjects who suffer from both febrile and afebrile seizures). Variants were filtered for frequency, evaluated through segregation and prediction tools, and classified according to ACMG guidelines.
RESULTS
Among 721 individuals tested with NGS or WES for neurological indications, 418 (58%) had a history of seizures, including 53 (7.3%) with fever-sensitive epilepsy. Pathogenic or likely pathogenic variants were identified in 30% of these cases. Notably, ATP6V0C variants accounted for 2/16 (12.5%) of all pathogenic/likely pathogenic findings and were identified in 3.8% of tested fever-sensitive epilepsy patients, ranking among the most frequently implicated genes in this cohort.
SIGNIFICANCE
Our findings support ATP6V0C as a relevant gene in the landscape of childhood epilepsies with fever sensitivity. The associated phenotype appears characterized by early febrile-triggered motor seizures, initially normal EEG followed by multifocal abnormalities, normal MRI and subsequent onset of neurodevelopmental impairment. These results highlight the importance of accurate molecular diagnosis in children presenting with fever-sensitive seizures, with potential implications for future precision therapies.
F. Tanganelli, Maria Francesca Di Feo, Francesca Madia et al.· Seizure· 0 citations
Abstract Objective Neurodevelopmental disorders (NDDs) and epilepsy are often associated. Increasing evidence highlights a pivotal role for pathogenic variants in genes encoding synaptic scaffolding proteins. Within this group, TANC2 has recently been implicated in intellectual developmental disorder with autistic features and language delay, with or without seizures; however, its full clinical spectrum and contribution to specific epileptic encephalopathies remain incompletely defined. Methods We describe the electroclinical and developmental features of three patients carrying truncating TANC2 variants identified through trio‐exome sequencing within the European collaborative platform NETRE. Clinical, neuropsychological, and EEG data were collected and compared with prior reports. Results Case #1 met Lennox–Gastaut syndrome (LGS) criteria, showing early drug resistance followed by partial cognitive recovery and sustained seizure control on felbamate monotherapy. Case #2 presented with ASD and multiple seizure types—including focal, atypical absence, and tonic—finally reaching prolonged remission and borderline intellectual functioning. Case #3 showed early‐onset, drug‐resistant polymorphic seizures with persistent bifrontal epileptiform discharges and severe developmental impairment, consistent with an LGS‐like phenotype, with seizure freedom achieved under a limited polytherapy regimen. Significance Our findings expand the electroclinical spectrum of TANC2‐related disorders, supporting a continuum ranging from NDD‐associated epilepsy to DEE, including LGS in selected patients. Plain Language Summary TANC2 is a gene involved in brain development and synaptic function. Changes in this gene have been linked to neurodevelopmental disorders, autism, intellectual disability, and epilepsy. We describe three individuals with previously unreported truncating TANC2 variants and different epilepsy phenotypes, including one patient fulfilling criteria for Lennox–Gastaut syndrome (LGS) and another with LGS‐like features. Although seizures were initially difficult to treat in some cases, seizure control was eventually achieved. These findings expand the known clinical spectrum of TANC2‐related disorders and suggest that selected patients may have a more favorable seizure course than expected.
L. Perilli, Carlotta Stipa, Gianmichele Villano et al.· Epilepsia Open· 0 citations
An integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.
Marina Boon, Meghan R. Mulligan, Jolijn J A Verseput et al.· American Journal of Human Ge...· 0 citations
This review synthesizes contemporary insights into the genetic and molecular pathophysiology of seizures and epilepsy, with emphasis on mechanisms that destabilize excitation–inhibition balance, promote epileptogenesis, and drive pharmacoresistance and supports more refined approaches to epilepsy classification and future precision medicine strategies.
Mohammad Reza Seyedtaghia, Jina Babanzadeh, Marcello Scala et al.· Epilepsia Open· 0 citations