Abstract We investigated whether intronic repeat expansions in the SAMD12 , STARD7 , and MARCHF6 genes are present in individuals with juvenile myoclonic epilepsy (JME) and tremor. Given that tremor is a shared feature with familial adult myoclonic epilepsy (FAME), we hypothesized that this phenotype may reflect a common genetic basis involving FAME‐associated pentanucleotide repeat expansions. The study included 31 individuals with JME and tremor (17/31 [54.8%] females, mean age at genetic testing = 34.4 ± 13.8 years) and 100 age‐ and sex‐matched healthy controls. Genomic DNA was analyzed using repeat‐primed polymerase chain reaction and fragment analysis to detect intronic TTTCA repeat expansions in the three established FAME‐associated genes. No pathogenic repeat expansions were identified in SAMD12 , STARD7 , or MARCHF6 among individuals with JME and tremor. The frequency of intronic pentanucleotide repeat expansions did not differ between cases and controls. This is a comprehensive analysis assessing three FAME‐associated repeat‐expansion loci in a clinically well‐characterized cohort of individuals with JME and tremor. Our findings do not support a major contribution of these FAME‐associated loci to tremor in this cohort, suggesting that those intronic repeats did not contribute to genetic susceptibility to the tremor in JME. Further studies are required to identify the factors associated with this phenotype.
Abstract A new type of epilepsy syndrome, an etiology‐specific epilepsy syndrome, was defined in 2022 in recognition of major advances in identifying the many genetic and acquired etiologies underlying the epilepsies. An etiology‐specific epilepsy syndrome refers to where a known etiology is associated with a distinctive epilepsy presentation, including age at seizure onset, seizure types, and other morbidities, such as learning difficulties or intellectual disability, psychiatric features, gut and musculoskeletal problems. However, as we understand more about a specific etiology, such as a gene, it is clear that many etiologies are associated not just with one epilepsy syndrome, but with a range of epilepsy syndromes. Different epilepsy syndromes due to an abnormality in the same gene may reflect different types of dysfunction caused by the specific pathogenic genetic variant. Here, we expand the concept because—knowing the genetic etiology is not enough to ensure optimal clinical care—it requires a more nuanced approach to ensure the patient is managed appropriately. We define the concept of an etiology‐specific spectrum of epilepsy syndromes (ESSES), which incorporates understanding the range of epilepsy syndromes that may be associated with a specific etiology. In some cases, a genetic etiology may be associated with a functional spectrum, such as pathogenic variants in an ion channel subunit that cause loss‐of‐function, gain‐of‐function, or mixed functional effects, each associated with specific epilepsy syndromes that may require different treatment approaches. With other genes, the functional effect may not yet be known, but their spectrum of epilepsy syndromes may be well established through genotype–phenotype studies. The concept of ESSES has the flexibility to grow in its scope with new insights gained from understanding the breadth of epilepsy syndromes associated with a specific etiology and the associated functional impact.
Abstract Objective During epileptogenesis, epileptic spikes emerge before seizures, yet the network mechanisms linking spike activity to seizure generation remain unclear. Previously, we showed that mitogen‐activated protein kinase kinase (MAP2K) inhibition reduces spiking in tetanus toxin (TeNT)‐injected rats. Here, we advanced the TeNT rat model to transition from spike to seizure networks to better understand the mechanisms underlying this process and determined the effect of MAP2K inhibition on both spikes and seizures. Methods Male rats received a single injection of TeNT into the somatosensory cortex (SC) or motor cortex (MC). Long‐term video‐electroencephalographic recordings over bilateral SC and MC were obtained for up to 140 days and analyzed using automated algorithms to quantify spike frequency, propagation, synchrony, and electrographic seizures. A subset of animals was treated orally with the MAP2K inhibitor CI‐1040 (250 mg/kg/day) on Days 14–35 to assess its effects on spike and seizure network formation. Results Low‐dose TeNT (60–120 ng/μL) injection into the SC produced progressive bihemispheric spiking without seizure development. In contrast, high‐dose TeNT (250 ng/μL) injection into the SC, but not MC, induced spontaneous electrographic seizures in five of eight animals. Before the first detected seizure, spikes were observed in both the ipsilateral and contralateral hemispheres. However, only animals whose propagation pattern became more synchronous developed seizures. Spike frequency did not differ between SC‐ and MC‐injected animals. Early inhibition of MAP2K using CI‐1040 reduced spike frequency and spike synchrony and was associated with an absence of detected seizures. Significance These findings demonstrate that the transition from interictal spikes to seizures in the rat sensory–motor system involves bihemispheric spike networks that transition into seizure networks. We show that SC is more prone to seizure development than MC and suggest that MAPK signaling contributes to bihemispheric spike synchronization, which could be important for seizure development.
Abstract Objective This study was undertaken to investigate the histopathological spectrum of drug‐resistant epilepsy (DRE) in a large Chinese surgical cohort using updated World Health Organization (WHO) and International League Against Epilepsy (ILAE) classifications, and to examine its associations with seizure onset age, lesion location, and postoperative seizure outcomes. Methods This retrospective, multicenter cohort study consecutively enrolled individuals who underwent resective epilepsy surgery between January 2011 and December 2020 at three Chinese hospitals. Histopathological diagnoses were updated by two independent neuropathologists based on the 2021 WHO and 2022 ILAE classifications, supplemented by immunohistochemistry and whole exome sequencing when indicated. Postoperative seizure outcome data were collected from medical records and telephone follow‐up, with the primary outcome defined as Engel class I at 1, 2, and 5 years after surgery, and Engel class Ia assessed as a secondary outcome. Results Of 2099 surgically treated individuals, 2068 with complete data were included. The predominant pathologies were hippocampal sclerosis (HS; 28.4%), epilepsy‐related tumors (20.7%), and malformations of cortical development (MCD; 15.4%). Childhood onset epilepsy was associated with MCD and HS, whereas adult onset cases favored non‐low‐grade epilepsy‐related tumors and vascular malformations, with developmental lesions presenting earliest. Whole exome sequencing confirmed mTOR pathway variants in 65.2% of focal cortical dysplasia II cases and SLC35A2 mutations in 62.5% of mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy cases. Among 293 individuals with complete 1‐, 2‐, and 5‐year outcome data (284 included in the adjusted prognostic model), no‐lesion cases had significantly lower odds of Engel class I at 5 years than HS (odds ratio [OR] = .21, 95% confidence interval [CI] = .08–.56, p = .002). Temporal lobe location predicted favorable Engel class I outcome (OR = 2.78, 95% CI = 1.31–5.90, p = .008). Engel class Ia results were not statistically significant. Significance Applying the updated WHO and ILAE classifications in this Chinese surgical cohort helps to characterize the pathological spectrum of DRE and may assist in postoperative outcome evaluation.
