ドラベ症候群

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.

INTRODUCTION: Dravet Syndrome (DS) is a severe early-onset epileptic encephalopathy associated with mutations in the alpha-1 sodium channel of the SCN1A gene. It is characterized by pharmacoresistant seizures and progressive deterioration in motor, cognitive, and communicative areas. Studies have shown significant alterations in language development, particularly in expressive language. METHODOLOGY: A descriptive case study was conducted. The sample consisted of six Spanish-speaking children with DS, aged 2 years 9 months to 6 years 5 months, one of whom had a comorbid diagnosis of autism spectrum disorder (ASD). All participants were living in Spain. The instruments used were the Battelle Developmental Inventory, the Reynell Developmental Language Scales III, the Peabody Picture Vocabulary Test (PPVT-5), and the MacArthur-Bates Communicative Development Inventory adapted for Down syndrome. RESULTS: The results showed delays across multiple developmental domains, including motor, adaptive, communication, and language abilities, with considerable interindividual variability. Across cases, global developmental and language-equivalent ages were below chronological age, although the magnitude and pattern of delay varied considerably across developmental domains and participants. Parent-report information obtained through the MacArthur-Bates Communicative Development Inventories complemented direct standardized assessment, particularly when behavioural or attentional difficulties limited the completion of some measures. DISCUSSION: The findings are consistent with previous literature indicating that expressive language may be more affected than receptive language in children with DS. The results also highlight substantial variability in the relationship between language abilities and broader developmental functioning, supporting the use of multidimensional and individualized assessment approaches. The role of speech-language therapists within interdisciplinary teams is particularly relevant for early identification and individualized intervention planning.

Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.

OBJECTIVE: Stiripentol and fenfluramine are approved treatments for Dravet syndrome (DS), but real-world data comparing their effectiveness and combined use remain limited. Our study aims to explore associations between treatment with stiripentol, fenfluramine, and their combination and clinical outcomes in patients with DS. METHODS: We retrospectively reviewed medical records of patients with genetically confirmed DS. Patients were classified into four treatment groups: stiripentol, fenfluramine, stiripentol + fenfluramine, other antiseizure medications. Seizure frequency, cognitive outcome, neuropsychiatric disorders, and movement disorders were compared across groups and according to age at treatment initiation and SCN1A genetic variant. Statistical analyses included Fisher's exact tests and Welch's one-way Analysis of Variance (p < 0.05). Post hoc analyses were conducted only for variables with a significant overall test (p < 0.05), using standardized residuals to identify which categories contributed most. We performed exploratory multivariable and sensitivity analyses to assess the consistency of our findings. Given the retrospective design and small subgroup sizes, analyses were considered exploratory. RESULTS: Sixty-six patients were included: stiripentol (n = 15), fenfluramine (n = 29), stiripentol + fenfluramine (n = 7), other antiseizure medications (n = 13). Exploratory analyses showed differences in seizure frequency distribution across treatment groups (p = 0.021), with lower seizure burden observed among patients receiving fenfluramine-containing regimens. This association remained significant after adjustment for age at last follow-up and disease duration (global p = 0.022). Differences in movement disorders observed in unadjusted analyses (p = 0.006) were attenuated after adjustment. No significant differences were observed for cognitive outcome (p = 0.081) or neuropsychiatric disorders (p = 0.152). Earlier initiation of stiripentol was descriptively associated with lower rates of movement disorders (p = 0.003), neuropsychiatric disorders (p = 0.013), and better cognitive outcomes (p = 0.013). Similarly, earlier initiation of fenfluramine was descriptively associated with more favorable cognitive outcomes (p < 0.001) and a lower prevalence of movement disorders (p = 0.028). These associations were substantially attenuated in sensitivity analyses accounting for age at assessment, disease duration and treatment era. SIGNIFICANCE: These preliminary findings suggest that fenfluramine-based regimens are associated with lower seizure burden in patients with DS. Associations between earlier initiation of syndrome-specific therapies and long-term developmental outcomes should be interpreted cautiously because of potential confounding by disease stage, treatment era, and non-random treatment allocation. Larger prospective studies are required to determine whether earlier treatment directly influences long-term developmental outcomes. PLAIN LANGUAGE SUMMARY: Patients receiving fenfluramine-based regimens had a lower seizure burden than those receiving other antiseizure medications. Earlier initiation of stiripentol or fenfluramine was associated with better cognitive and motor outcomes, but these associations were substantially influenced by age, disease duration, and treatment era. Larger prospective studies are needed to determine whether earlier treatment independently influences long-term developmental outcomes.

OBJECTIVE: To systematically review the current research progress on clobazam in pediatric antiepileptic therapy, focusing on its pharmacological mechanisms, pharmacokinetic properties, clinical efficacy, safety profile, and approaches to individualized treatment, with particular emphasis on the influence of CYP2C19 genetic polymorphisms on pharmacokinetics and therapeutic outcomes, and to provide a comprehensive reference for the rational clinical use of clobazam. METHODS: This article comprehensively reviews the current research progress on clobazam in pediatric antiepileptic therapy, including evidence of efficacy across different epilepsy syndromes, strategies for managing drug-drug interactions, and individualized dosing regimens based on genotyping and therapeutic drug monitoring. RESULTS: Clobazam is a 1,5-benzodiazepine used as an antiseizure medication. Compared with classical 1,4-benzodiazepines, it demonstrates greater efficacy and fewer sedative adverse effects. Clobazam was approved by the U.S. Food and Drug Administration (FDA) in 2011 as an adjunctive therapy for seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥2 years. Since then, it has been increasingly used as adjunctive therapy for several pediatric epilepsy syndromes, including Dravet syndrome (DS), epilepsy with myoclonic-atonic seizures (EMAS), and epileptic encephalopathy with spike-wave activation during sleep. CYP2C19 genetic polymorphisms significantly influence its pharmacokinetics and therapeutic outcomes. Across the reviewed studies, adjunctive clobazam achieved ≥50% seizure reduction in approximately 53% of children and seizure freedom in approximately 24%. Efficacy was highest in LGS, supported by randomized controlled trials, while evidence for other syndromes was largely observational. CYP2C19 poor metabolizer status significantly increased N-desmethylclobazam exposure, supporting genotype-guided dose initiation. CONCLUSION: Clobazam demonstrates consistent efficacy as adjunctive therapy in pediatric drug-resistant epilepsy, with the strongest evidence supporting its use in LGS. Individualized treatment informed by CYP2C19 genotyping and therapeutic drug monitoring can optimize clinical outcomes. This review provides a comprehensive reference for the rational clinical use of clobazam.