ミオクロニー欠神てんかん

BACKGROUND: Pathogenic variants in TAF1 have previously been associated with X-linked intellectual disability and X-linked dystonia-parkinsonism. Epilepsy is observed in approximately 24.4% of affected individuals, ranging from focal seizures to generalized seizures including either tonic-clonic, tonic, myoclonic, atonic or absences. To date, no cases of infantile epileptic spasm syndrome (IESS) have been associated with this neurogenetic condition. In this study, we are aimed at investigating the association between TAF1 and IESS. METHODS: We performed whole-exome sequencing in two unrelated Chinese patients with IESS. Functional consequences were assessed using in vitro overexpression assays, transcriptome profiling of Neuro-2a cells with stable TAF1 knockdown, morphological, and electrophysiological analyses in primary mouse cortical neurons. RESULTS: We identified two novel TAF1 missense variants (c.236C > A, p.T79N; c.4771G > A, p.D1591N) in the two patients. Both novel TAF1 missense variants led to reduced TAF1 protein expression, suggesting a loss-of-function mechanism. Transcriptome analysis revealed that TAF1 deficiency resulted in significant downregulation of key neuronal genes involved in axon guidance and epileptogenesis, including Kcnn2, Kcna4, Draxin, and Lgi1. In primary mouse cortical neurons, TAF1 knockdown markedly impaired neurite outgrowth and increased neuronal excitability. CONCLUSION: Our findings establish TAF1 missense variants as a novel cause of IESS-a previously unrecognized phenotype-thereby expanding the epileptic phenotype of TAF1-related disorders. Furthermore, we demonstrate that TAF1 deficiency contributes to disease pathogenesis by impairing neuronal development and increasing neuronal excitability, likely through the downregulation of Kcnn2, Kcna4, Draxin, and Lgi1.

BACKGROUND: Dravet syndrome (DS) is a severe and treatment-resistant epileptic encephalopathy, most commonly caused by de novo mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene. Patients with DS often present with febrile seizures. It has been reported that Scn1a mutant mice have the risk for hyperthermia-induced clonic seizures similar to those observed in patients with DS. Using our heating protocol with an incubator, we evaluated the effects of antiseizure medications on the incidence of hyperthermia-induced clonic seizures in mutant Scn1a knock-in (KI)/+ mice. METHODS: For clonic seizure induction in Scn1a KI/+ mice, each mouse was placed into an incubator (38°C-40°C) and observed for 15 min. Antiseizure medications were administered orally 30 min prior to the experiment. The time to seizure onset and the incidence of clonic seizures were analyzed to evaluate and compare the antiseizure effects among treatment groups. RESULTS: Our incubation system increased the body temperature of mice and induced clonic seizures in Scn1a KI/+ mice. Clobazam (CLB) and valproate (VPA) significantly reduced the incidence of hyperthermia-induced clonic seizures in Scn1a KI/+ mice, with 50% effective dose (ED50) values of 1.94 mg/kg (95% confidence interval [CI]: 0.93-3.89 mg/kg) and 255.87 mg/kg (95% CI: 188.66-356.85 mg/kg) respectively, and prolonged the time to seizure onset. In contrast, lamotrigine (LTG), a sodium channel blocker, did not reduce the incidence of hyperthermia-induced seizures. CLB and LTG did not affect the body temperature. VPA decreased the body temperature compared to the vehicle-treated mice before and after incubation. CONCLUSION: These results reflect clinical findings that CLB and VPA suppress, but LTG does not suppress seizures in patients with DS. Our data demonstrate the validity of our test system to induce hyperthermia-induced seizures and to evaluate the efficacy of antiseizure medications in Scn1a KI/+ mice.

OBJECTIVE: To determine the extent to which electroclinical information available at initial evaluation allows classification of idiopathic generalized epilepsy (IGE) syndromes, and to assess the contributions of seizure semiology and age at seizure onset to early syndromic diagnosis. METHODS: We prospectively analyzed a cohort of patients with new-onset seizures who underwent a structured clinical evaluation, including detailed history-taking, 3-h video-EEG, and epilepsy-protocol MRI. Seizure semiology was assessed at three levels: index seizure, initial seizure type, and seizure types identified at initial evaluation. Syndromic classification followed International League Against Epilepsy criteria. Final electroclinical diagnosis, established after longitudinal follow-up, served as reference. Within patients ultimately diagnosed with one of the four IGE syndromes, baseline data were used to determine whether the final syndrome could be assigned at initial evaluation. RESULTS: Of 2699 patients evaluated, 498 (18.4%) met criteria for genetic generalized epilepsy, of whom 401 (80.5%) were classified as having one of the IGE syndromes. Based on initial evaluation, the correct syndrome could be assigned in 366 patients (91.3%), whereas 7 (1.7%) would have been misclassified and 28 (7.0%) were not assignable. Non-assignability was confined to absence epilepsies, reflecting overlap between childhood (CAE) and juvenile absence epilepsy (JAE), whereas misclassification occurred only in juvenile myoclonic epilepsy (JME) presenting with isolated generalized tonic-clonic (GTC) seizures. Classification based on the index seizure alone showed limited accuracy (63.6%), whereas incorporation of seizure types identified through structured history improved classification to 95.0%. Myoclonic seizures were highly specific for JME, whereas absence and GTC seizures required integration with additional features. Age at seizure onset strongly differentiated CAE from JAE (AUC 0.935). SIGNIFICANCE: Electroclinical classification of IGE syndromes is frequently achievable at initial evaluation when based on seizure semiology and age at onset. When classification is not possible, limitations follow predictable electroclinical patterns, supporting a structured, history-driven diagnostic approach. PLAIN LANGUAGE SUMMARY: This study examined how accurately doctors can identify specific types of generalized epilepsy when patients are first evaluated. Among 401 patients with generalized epilepsy, the correct epilepsy syndrome could be identified in more than 90% at the first visit. Looking beyond the first seizure and asking about all seizure types together with age at seizure onset greatly improved diagnosis. While some overlap exists between specific types (like childhood versus juvenile absence epilepsy), a thorough clinical evaluation from the start provides reliable diagnostic direction for patients and supports early and accurate diagnosis.

The extracellular milieu, including extracellular vesicles (EVs), plays a pivotal role in brain development. In this study, we sought to elucidate the pathogenesis of progressive myoclonus epilepsy type 1 (EPM1), a disease caused by mutations in the CSTB gene, using cerebral organoids (COs) derived from patient cells. The results demonstrate that EPM1 COs display increased electrophysiological activity and disrupted excitatory/inhibitory (E/I) balance. Single-cell RNA sequencing analysis of ventral EPM1-COs revealed an abnormal specification of progenitor fate, with a shift toward dorsal neuron identities. We demonstrated that this misspecification is driven by a functional alteration of the ventral signaling niche, resulting from impaired EV dynamics and altered protein cargo. Mechanistically, we identified Sonic Hedgehog (SHH) as a direct physical interactor of CSTB and demonstrated that CSTB deficiency leads to reduced SHH content and secretion. Our findings establish CSTB as a safeguard of ventral patterning and identify the CSTB-SHH-EV axis as a potential therapeutic target for mitigating the E/I imbalance associated with EPM1.